The autoimmune disease type 1 diabetes is characterized by effector T-cell responses to pancreatic β-cell–derived peptides presented by HLA class I and class II molecules, leading ultimately to β-cell demise and insulin insufficiency. Although a given HLA molecule presents a vast array of peptides, only those recognized by T cells are designated as epitopes. Given their intimate link to etiology, the discovery and characterization of T-cell epitopes is a critical aspect of type 1 diabetes research. Understanding epitope recognition is also crucial for the pursuit of antigen-specific immunotherapies and implementation of strategies for T-cell monitoring. For these reasons, a cataloging and appraisal of the T-cell epitopes targeted in type 1 diabetes was completed over a decade ago, providing an important resource for both the research and the clinical communities. Here we present a much needed update and reappraisal of this earlier work and include online supplementary material where we cross-index each epitope with its primary references and Immune Epitope Database (IEDB) identifier. Our analysis includes a grading scale to score the degree of evidence available for each epitope, which conveys our perspective on several useful criteria for epitope evaluation. While providing an efficient summary of the arguably impressive current state of knowledge, this work also brings to light several deficiencies. These include the need for improved epitope validation, as few epitopes score highly by the criteria employed, and the dearth of investigations of the epitopes recognized in the context of several understudied type 1 diabetes–associated HLA molecules.

The key role of autoimmune CD8+ and CD4+ T cells in the orchestration and final effector phase of β-cell destruction in type 1 diabetes is widely accepted (1). Based on this knowledge, T cells are expected to provide useful biomarkers, complementary to autoantibodies, for staging type 1 diabetes progression and monitoring regression following immunotherapy. The specificity of the autoimmune T cells toward β-cells is shaped through their recognition of peptides presented by HLA class I and class II molecules expressed on the surface of β-cells and/or antigen-presenting cells. The identification of the T-cell epitopes, i.e., those HLA-bound peptides recognized by autoreactive T cells, is therefore a matter of major effort in the field, as it provides critical information for detecting the corresponding T cells for disease-staging purposes, for developing antigen-specific immunotherapies, and for understanding disease pathogenesis. The increasing number of articles reporting the identification, characterization, or use of human islet–derived T-cell epitopes throughout recent years reflects these efforts (Fig. 1A and D), as does the continued discovery of new epitopes (Fig. 1B, C, E, and F). The pace of growth of this literature calls for a comprehensive assessment of the information available, as the first and only systematic review compiling this information dates back to 2007 (2). Additional reasons for updating this body of data include the advent of three relevant advances that were not available at that time. The first advance is the discovery of neo-epitopes generated by different mechanisms (3). The second is the efforts launched by the Network for Pancreatic Organ Donors with Diabetes (nPOD) and others, which have provided increased access to disease-proximal tissues, i.e., pancreas, isolated islets, and pancreatic lymph nodes (pLNs), while previous studies were largely confined to peripheral blood (4). This development also calls for a reappraisal of the strategy used to grade the level of evidence that defines a given epitope as such. Third, the Immune Epitope Database (IEDB) (www.iedb.org) now provides a comprehensive and prospective compilation of T-cell (and B-cell) epitopes relevant not only to type 1 diabetes and other autoimmune conditions but also to allergy, infectious disease, and transplantation (5). An updated assessment therefore should not be redundant with the IEDB information but, rather, complement it with additional elements, e.g., by grading the level of evidence for the epitopes and cross-referencing them with IEDB entries. These considerations have guided the epitope analysis presented herein.

Figure 1

Year-by-year and cumulative summary of the articles and epitopes examined in this work. AC: HLA class I–restricted epitopes. DF: HLA class II–restricted epitopes. A: The articles represented in Table 1 were categorized by year of publication and the corresponding cumulative article numbers are depicted in A. For articles having both an e-publication date and a print date in PubMed, the earlier date was used to assign the year of publication. See Supplementary Table 1 for the PMID numbers for all of the 65 articles included in A. B and C: The number of new HLA class I–restricted epitopes reported in each of the indicated years is depicted in B, with the corresponding cumulative epitope numbers shown in C, for a total of 140 epitopes reported by the end of 2018. D: The articles represented in Table 2 were categorized by year of publication and the corresponding cumulative article numbers are depicted in D. See Supplementary Table 2 for the PMID numbers for all of the 100 articles included in D. E and F: The number of new HLA class II–restricted epitopes reported in each of the indicated years is depicted in E, with the corresponding cumulative epitope numbers shown in F, for a total of 418 epitopes reported by the end of 2018. Note that the cutoff for inclusion in our analysis was a publication date up to 9 July 2019. Given the partial nature of the data for 2019, the corresponding articles and epitopes are not included in Figure 1.

Figure 1

Year-by-year and cumulative summary of the articles and epitopes examined in this work. AC: HLA class I–restricted epitopes. DF: HLA class II–restricted epitopes. A: The articles represented in Table 1 were categorized by year of publication and the corresponding cumulative article numbers are depicted in A. For articles having both an e-publication date and a print date in PubMed, the earlier date was used to assign the year of publication. See Supplementary Table 1 for the PMID numbers for all of the 65 articles included in A. B and C: The number of new HLA class I–restricted epitopes reported in each of the indicated years is depicted in B, with the corresponding cumulative epitope numbers shown in C, for a total of 140 epitopes reported by the end of 2018. D: The articles represented in Table 2 were categorized by year of publication and the corresponding cumulative article numbers are depicted in D. See Supplementary Table 2 for the PMID numbers for all of the 100 articles included in D. E and F: The number of new HLA class II–restricted epitopes reported in each of the indicated years is depicted in E, with the corresponding cumulative epitope numbers shown in F, for a total of 418 epitopes reported by the end of 2018. Note that the cutoff for inclusion in our analysis was a publication date up to 9 July 2019. Given the partial nature of the data for 2019, the corresponding articles and epitopes are not included in Figure 1.

Epitope Cataloguing

To catalog all reported T-cell epitopes of potential relevance to human type 1 diabetes, we used a combination of search strategies, based on both PubMed and IEDB. Our goal was not to validate a single search strategy that would capture all published relevant T-cell epitopes but, rather, to use a combination of approaches to ensure a comprehensive coverage. Although IEDB includes T-cell epitopes that are submitted by individual investigators in addition to those extracted from the published literature by IEDB staff, we limited our analysis to published epitopes. In addition to the increased confidence afforded by peer reviewing, our detailed description of each epitope often required information not available in IEDB to be extracted from each reporting article, e.g., in the case of ex vivo T-cell studies, whether T-cell frequency differences between patients with type 1 diabetes and control subjects were statistically supported.

To harvest T-cell epitopes of potential relevance to type 1 diabetes from the IEDB, we first conducted a search at the level of protein antigens (rather than at the level of peptide epitopes) that included the following criteria: human proteins, T-cell assays only, positive assays only, MHC class I (for CD8+ T-cell epitopes) or MHC class II only (for CD4+ T-cell epitopes), any host, and insulin-dependent diabetes related. In some instances, we made the judgment to omit certain epitope sources. For example, peptides derived from claudin-17, tafazzin, and glucose-6-phosphatase were only reported as cross-reactive targets of T cells specific for GAD65 (6) or islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP) (7) and were thus excluded. The proteins returned from our IEDB searches were then individually queried to compile epitope lists using similar criteria: T-cell assays only, positive assays only, MHC class I or class II only, and any host (to capture epitopes of human proteins discovered in model systems such as HLA-transgenic [Tg] mice). Epitopes with nonhuman MHC restrictions or disease associations other than insulin-dependent diabetes, e.g., stiff person syndrome, were eliminated. We then supplemented this information by searching PubMed for publications reporting relevant epitopes that had not yet been included in the IEDB, using various combinations of these search terms: diabetes, T cell, peptide, epitope, and CD8 or CD4. These epitopes were referred to IEDB staff for curation to ensure that each epitope in our analysis could be cross-referenced with an IEDB identification number. To minimize issues of reproducibility and conflicts in T-cell epitope data (8), we recommend inclusion of the indicated IEDB numbers in future publications. All epitopes and supporting references were then compiled into comprehensive epitope tables (Supplementary Tables 1 and 2), organized by the antigen from which they were derived. The cutoff for inclusion in our analysis was a publication date up to 9 July 2019. Differing from the previous work (2), we included all references providing important information about a given epitope, which are listed in chronological order of publication, including multiple references from a single group. Summary tables, in which each epitope was collapsed to a single line, were then constructed (Tables 1 and 2). In all of these tables, the names of the parent antigens are abbreviated according to the manner in which they are generally referred to in the literature. Supplementary Table 3 provides complete nomenclature information for each antigen, including the protein name prescribed by the UniProt consortium (www.uniprot.org) (9).

Table 1

CD8+ T-cell epitopes in type 1 diabetes

Antigen (gene)PositionSequenceIEDB#aMHCHuman islets, pLNsbHuman blood, spleenbHLA-Tg mousebNPPcEvidencedReporting articlese
CHGA (CHGA10–19 LLCAGQVTAL 880821 A*02:01  Yes   D+ 
   43–52 TLSKPSPMPV 884674 A*02:01  Yes   D+ 
   344–352 KMDQLAKEL 952211 A*02:01  Yes  Yes B+ 
GAD65 (GAD23–11 SPGSGFWSF 177987 B*07:02  Yes Yes Yes B+ 
   100–108 ACDGERPTL 177585 B*07:02  Yes Yes Yes B+ 
   110–118 FLQDVMNIL 102433 A*02:01  Yes Yes Yes B+ 
   114–122 VMNILLQYV 104336 A*02:01  Yes   C− 
   114–123 VMNILLQYVV 102908 A*02:01 Yes Yes Yes Yes A+ 16 
   141–149 LLQEYNWEL 102620 A*02:01  Yes Yes Yes B+ 
   159–167 ILMHCQTTL 104844 A*02:01  Yes Yes Yes B+ 
   175–184 HPRYFNQLST 177734 B*07:02  Yes Yes Yes B+ 
   255–263 RFKMFPEVK 104218 A3  Yes   C− 
   255–263 RFKMFPEVK 104218 A11  Yes   C− 
   269–277 ALP(R→Cit)LIAFT 436368 A2  Yes   C– 
   277–285 TSEHSHFSL 104317 B15  Yes   C– 
   277–285 TSEHSHFSL 104317 B35  Yes   C– 
   311–320 IPSDLERRIL 177779 B*07:02  Yes Yes Yes B+ 
   476–484 ELAEYLYNI 104767 A*02:01  Yes Yes Yes B+ 
   498–506 KPQHTNVCF 177813 B*07:02  Yes Yes Yes B+ 
   530–538 APVIKARMM 177606 B*07:02  Yes Yes Yes B+ 
   536–545 RMMEYGTTMV 102769 A*02:01  Yes Yes Yes B+ 
GFAP (GFAP143–151 NLAQDLATV 115871 A*02:01  Yes   D+ 
   192–200 SLEEEIRFL 115968 A*02:01  Yes   D+ 
   214–222 QLARQQVHV 115919 A*02:01  Yes   D+ 
IA-2 (PTPRN172–180 SLSPLQAEL 101245 A*02:01  Yes   D+ 
   180–188 LLPPLLEHL 101026 A*02:01  Yes   D+ 
   482–490 SLAAGVKLL 101237 A*02:01  Yes   D+ 
   790–798 TIADFWQMV 102844 A*02:01  Yes Yes Yes B+ 
   797–805 MVWESGCTV 140054 A*02:01 Yes Yes   C+ 
   805–813 VIVMLTPLV 102899 A*02:01  Yes Yes Yes B+ 
   830–839 SLYHVYEVNL 102811 A*02:01  Yes Yes Yes B+ 
   925–933 VLN(R→Cit)MAKGV 441419 A2  Yes   C– 
   962–970 ALTAVAEEV 102306 A*02:01  Yes Yes Yes B+ 
IAPP (IAPP5–13 KLQVFLIVL 100981 A*02:01 Yes Yes   
   9–17 FLIVLSVAL 100844 A*02:01  Yes   D+ 
IGRP (G6PC2152–160 FLWSVFWLI 105191 A*02:01  Yes   D+ 
   211–219 NLFLFLFAV 105409 A2  Yes   D+ 
   215–223 FLFAVGFYL 100843 A*02:01  Yes Yes  D+ 
   222–230 YLLLRVLNI 105617 A2  Yes   D+ 
   228–236 LNIDLLWSV 103368 A*02:01  Yes   D+ 
   258–266 GLV(R→Cit)NLGVL 437684 A2  Yes   C– 
   265–273 VLFGLGFAI 103705 A*02:01 Yes Yes Yes  C+ 18 
   293–301 RLLCALTSL 101199 A*02:01  Yes Yes  D+ 
INS (INS2–10 (L2–L10) ALWMRLLPL 100725 A*02:01  Yes   D+ 
   2–11 (L2–L11) ALWMRLLPLL 105674 A*02:01  Yes Yes Yes A– 
   2–11 (L2–L11) ALWMRLLPLL 105674 A24  Yes  Yes B+ 
   2–11 (L2–L11) ALWMRLLPLL 105674 B8  Yes  Yes B+ 
   3–11 (L3–L11) LWMRLLPLL 105950 A*24:02  Yes  Yes A– 
   4–13 (L4–L13) WMRLLPLLAL 106187 B7  Yes  Yes B+ 
   6–14 (L6–L14) RLLPLLALL 103557 A*02:01  Yes Yes Yes A– 
   6–16 (L6–L16) RLLPLLALLAL 115471 A2  Yes  Yes B+ 
   8–16 (L8–L16) LPLLALLAL 105936 B*07:02  Yes   D+ 
   9–18 (L9–L18) PLLALLALWG 159293 A3  Yes  Yes B+ 
   14–23 (L14–L23) LALWGPDPAA 115337 A2  Yes Yes Yes A– 
   15–24 (L15–L24) ALWGPDPAAA 103041 A*02:01 Yes Yes Yes Yes A+ 21 
   15–25 (L15–B1) ALWGPDPAAAF 115182 A1  Yes  Yes B+ 
   15–25 (L15–B1) ALWGPDPAAAF 115182 A24  Yes  Yes B+ 
   17–24 (L17–L24) WGPDPAAA 103728 A*02:01  Yes  Yes B+ 
   29–38 (B5–B14) HLCGSHLVEA 102515 A*02:01  Yes Yes Yes B+ 
   30–39 (B6–B15) LCGSHLVEAL 106593 A*02:01  Yes   D+ 
   33–42 (B9–B18) SHLVEALYLV 104248 A*02:01  Yes Yes Yes A– 
   34–42 (B10–B18) HLVEALYLV 100920 A*02:01 Yes Yes Yes Yes A+ 22 
   38–46 (B14–B22) ALYLVCGER 103803 A3  Yes  Yes B+ 
   38–46 (B14–B22) ALYLVCGER 103803 A11  Yes  Yes B+ 
   39–47 (B15–B23) LYLVCGERG 102639 A*24:02  Yes   C– 
   39–48 (B15–B24) LYLVCGERGF 106637 A24  Yes  Yes B+ 
   41–50 (B17–B26) LVCGERGFFY 106631 A1  Yes  Yes B+ 
   41–50 (B17–B26) LVCGERGFFY 106631 A3  Yes  Yes B+ 
   41–50 (B17–B26) LVCGERGFFY 106631 A11  Yes  Yes B+ 
   42–51 (B18–B27) VCGERGFFYT 102877 A1  Yes  Yes B+ 
   42–51 (B18–B27) VCGERGFFYT 102877 A*02:01  Yes Yes Yes B+ 
   42–51 (B18–B27) VCGERGFFYT 102877 B8  Yes  Yes B+ 
   42–51 (B18–B27) VCGERGFFYT 102877 B18  Yes  Yes B+ 
   44–51 (B20–B27) GERGFFYT 105816 A1  Yes  Yes B+ 
   44–51 (B20–B27) GERGFFYT 105816 B8  Yes  Yes B+ 
   45–53 (B21–B29) ERGFFYTPK 106399 A3  Yes  Yes B+ 
   49–57 (B25–C1) FYTPKTRRE 105799 B8  Yes  Yes B+ 
   51–61 (B27–C5) TPKTRREAEDL 106918 B8  Yes  Yes B+ 
   76–84 (C20–C28) SLQPLALEG 101242 A*02:01  Yes Yes Yes A– 
   76–84 (C20–C28) SLQPLALEG 101242 A3  Yes  Yes B+ 
   79–88 (C23–C32) PLALEGSLQK 159292 A3  Yes  Yes B+ 
   81–89 (C25–C33) ALEGSLQKR 104727 A*02:01   Yes Yes 
   85–94 (C29–A5) SLQKRGIVEQ 101241 A*02:01  Yes Yes Yes A– 
   90–99 (A1–A10) GIVEQCCTSI 100882 A*02:01  Yes Yes Yes A– 
   101–109 (A12–A20) SLYQLENYC 101248 A*02:01  Yes Yes Yes A– 
ISL-1 (ISL1276–284 GLQANPVEV 952138 A*02:01 Yes Yes  Yes 
KCNK16 (KCNK16129–137 ALLGIPLNV 952014 A*02:01  Yes  Yes B+ 
KIF1A (KIF1A1347–1355 VLDTSVAYV 779283 A*02:01  Yes  Yes B+ 
PC2 (PCSK230–38 FTNHFLVEL 952113 A*02:01  Yes  Yes B+ 
S100β (S100B10–18 ALIDVFHQY 562065 A*02:01  Yes Yes Yes B+ 
   20–28 GREGDKHKL 910732 A*02:01  Yes Yes Yes B+ 
SCG5 (SCG5186–195 YLQGQRLDNV 952620 A*02:01  Yes  Yes B+ 
UCN3 (UCN31–9 MLMPVHFLL 952274 A*02:01 Yes Yes  Yes 
VTDB (GC211–219 LLTTLSNRV 767640 A*02:01  Yes Yes  D+ 
   235–243 NLIKLAQV 767652 A*02:01  Yes Yes  D+ 
ZnT8 (SLC30A816–24 KMYAFTLES 171844 A*02:01  Yes Yes Yes B+ 
   16–25 KMYAFTLESV 504008 A*02:01  Yes   D+ 
   93–101 HIAGSLAVV 168764 A2  Yes Yes Yes B+ 
   107–115 LLIDLTSFL 169149 A*02:01  Yes Yes  C– 
   107–116 LLIDLTSFLL 504015 A*02:01  Yes Yes Yes B+ 
   110–118 DLTSFLLSL 168356 A*02:01  Yes   D+ 
   114–123 FLLSLFSLWL 168578 A*02:01  Yes Yes Yes B+ 
   115–123 LLSLFSLWL 172188 A*02:01  Yes Yes Yes A– 
   140–148 EILGALLSI 168356 A*02:01  Yes   D+ 
   141–149 ILGALLSIL 168867 A*02:01  Yes   D+ 
   145–153 LLSILCIWV 172186 A*02:01   Yes  
   153–161 VVTGVLVYL 170038 A*02:01  Yes Yes Yes B+ 
   165–173 RLLYPDYQI 173061 A*02:01  Yes Yes Yes B+ 
   173–181 IQATVMIIV 171556 A*02:01  Yes Yes Yes B+ 
   177–186 VMIIVSSLAV 504065 A*02:01  Yes Yes Yes B+ 
   185–194 AVAANIVLTV 168235 A*02:01  Yes Yes Yes A– 
   186–194 VAANIVLTV 173562 A*02:01 Yes Yes Yes Yes A+ 
   200–208 CLGHNHKEV 503971 A*02:01  Yes   D+ 
   221–229 ALGDLFQSI 168159 A*02:01  Yes Yes Yes B+ 
   228–236 SISVLISAL 169725 A2  Yes Yes Yes B+ 
   245–254 KIADPICTFI 504005 A*02:01  Yes   D+ 
   253–261 FIFSILVLA 171037 A*02:01  Yes Yes Yes B+ 
   253–261 FIF(S→pS)ILVLA 437274 A2  Yes     C– 
   257–266 ILVLASTITI 168881 A2  Yes Yes Yes B+ 
   266–274 ILKDFSILL 168874 A*02:01  Yes Yes Yes B+ 
   273–282 LLMEGVPKSL 169153 A*02:01  Yes   D+ 
   280–288 KSLNYSGVK 171933 A*02:01  Yes Yes Yes B+ 
   281–290 SLNYSGVKEL 169744 A*02:01  Yes   D+ 
   291–300 ILAVDGVLSV 168865 A*02:01  Yes Yes Yes B+ 
   292–300 LAVDGVLSV 172015 A*02:01  Yes   D+ 
   299–308 SVHSLHIWSL 169790 A*02:01  Yes   D+ 
   314–322 ILSAHVATA 168880 A*02:01  Yes   D+ 
   343–351 TMHSLTIQM 173491 A*02:01  Yes Yes Yes B+ 
Antigen (gene)PositionSequenceIEDB#aMHCHuman islets, pLNsbHuman blood, spleenbHLA-Tg mousebNPPcEvidencedReporting articlese
CHGA (CHGA10–19 LLCAGQVTAL 880821 A*02:01  Yes   D+ 
   43–52 TLSKPSPMPV 884674 A*02:01  Yes   D+ 
   344–352 KMDQLAKEL 952211 A*02:01  Yes  Yes B+ 
GAD65 (GAD23–11 SPGSGFWSF 177987 B*07:02  Yes Yes Yes B+ 
   100–108 ACDGERPTL 177585 B*07:02  Yes Yes Yes B+ 
   110–118 FLQDVMNIL 102433 A*02:01  Yes Yes Yes B+ 
   114–122 VMNILLQYV 104336 A*02:01  Yes   C− 
   114–123 VMNILLQYVV 102908 A*02:01 Yes Yes Yes Yes A+ 16 
   141–149 LLQEYNWEL 102620 A*02:01  Yes Yes Yes B+ 
   159–167 ILMHCQTTL 104844 A*02:01  Yes Yes Yes B+ 
   175–184 HPRYFNQLST 177734 B*07:02  Yes Yes Yes B+ 
   255–263 RFKMFPEVK 104218 A3  Yes   C− 
   255–263 RFKMFPEVK 104218 A11  Yes   C− 
   269–277 ALP(R→Cit)LIAFT 436368 A2  Yes   C– 
   277–285 TSEHSHFSL 104317 B15  Yes   C– 
   277–285 TSEHSHFSL 104317 B35  Yes   C– 
   311–320 IPSDLERRIL 177779 B*07:02  Yes Yes Yes B+ 
   476–484 ELAEYLYNI 104767 A*02:01  Yes Yes Yes B+ 
   498–506 KPQHTNVCF 177813 B*07:02  Yes Yes Yes B+ 
   530–538 APVIKARMM 177606 B*07:02  Yes Yes Yes B+ 
   536–545 RMMEYGTTMV 102769 A*02:01  Yes Yes Yes B+ 
GFAP (GFAP143–151 NLAQDLATV 115871 A*02:01  Yes   D+ 
   192–200 SLEEEIRFL 115968 A*02:01  Yes   D+ 
   214–222 QLARQQVHV 115919 A*02:01  Yes   D+ 
IA-2 (PTPRN172–180 SLSPLQAEL 101245 A*02:01  Yes   D+ 
   180–188 LLPPLLEHL 101026 A*02:01  Yes   D+ 
   482–490 SLAAGVKLL 101237 A*02:01  Yes   D+ 
   790–798 TIADFWQMV 102844 A*02:01  Yes Yes Yes B+ 
   797–805 MVWESGCTV 140054 A*02:01 Yes Yes   C+ 
   805–813 VIVMLTPLV 102899 A*02:01  Yes Yes Yes B+ 
   830–839 SLYHVYEVNL 102811 A*02:01  Yes Yes Yes B+ 
   925–933 VLN(R→Cit)MAKGV 441419 A2  Yes   C– 
   962–970 ALTAVAEEV 102306 A*02:01  Yes Yes Yes B+ 
IAPP (IAPP5–13 KLQVFLIVL 100981 A*02:01 Yes Yes   
   9–17 FLIVLSVAL 100844 A*02:01  Yes   D+ 
IGRP (G6PC2152–160 FLWSVFWLI 105191 A*02:01  Yes   D+ 
   211–219 NLFLFLFAV 105409 A2  Yes   D+ 
   215–223 FLFAVGFYL 100843 A*02:01  Yes Yes  D+ 
   222–230 YLLLRVLNI 105617 A2  Yes   D+ 
   228–236 LNIDLLWSV 103368 A*02:01  Yes   D+ 
   258–266 GLV(R→Cit)NLGVL 437684 A2  Yes   C– 
   265–273 VLFGLGFAI 103705 A*02:01 Yes Yes Yes  C+ 18 
   293–301 RLLCALTSL 101199 A*02:01  Yes Yes  D+ 
INS (INS2–10 (L2–L10) ALWMRLLPL 100725 A*02:01  Yes   D+ 
   2–11 (L2–L11) ALWMRLLPLL 105674 A*02:01  Yes Yes Yes A– 
   2–11 (L2–L11) ALWMRLLPLL 105674 A24  Yes  Yes B+ 
   2–11 (L2–L11) ALWMRLLPLL 105674 B8  Yes  Yes B+ 
   3–11 (L3–L11) LWMRLLPLL 105950 A*24:02  Yes  Yes A– 
   4–13 (L4–L13) WMRLLPLLAL 106187 B7  Yes  Yes B+ 
   6–14 (L6–L14) RLLPLLALL 103557 A*02:01  Yes Yes Yes A– 
   6–16 (L6–L16) RLLPLLALLAL 115471 A2  Yes  Yes B+ 
   8–16 (L8–L16) LPLLALLAL 105936 B*07:02  Yes   D+ 
   9–18 (L9–L18) PLLALLALWG 159293 A3  Yes  Yes B+ 
   14–23 (L14–L23) LALWGPDPAA 115337 A2  Yes Yes Yes A– 
   15–24 (L15–L24) ALWGPDPAAA 103041 A*02:01 Yes Yes Yes Yes A+ 21 
   15–25 (L15–B1) ALWGPDPAAAF 115182 A1  Yes  Yes B+ 
   15–25 (L15–B1) ALWGPDPAAAF 115182 A24  Yes  Yes B+ 
   17–24 (L17–L24) WGPDPAAA 103728 A*02:01  Yes  Yes B+ 
   29–38 (B5–B14) HLCGSHLVEA 102515 A*02:01  Yes Yes Yes B+ 
   30–39 (B6–B15) LCGSHLVEAL 106593 A*02:01  Yes   D+ 
   33–42 (B9–B18) SHLVEALYLV 104248 A*02:01  Yes Yes Yes A– 
   34–42 (B10–B18) HLVEALYLV 100920 A*02:01 Yes Yes Yes Yes A+ 22 
   38–46 (B14–B22) ALYLVCGER 103803 A3  Yes  Yes B+ 
   38–46 (B14–B22) ALYLVCGER 103803 A11  Yes  Yes B+ 
   39–47 (B15–B23) LYLVCGERG 102639 A*24:02  Yes   C– 
   39–48 (B15–B24) LYLVCGERGF 106637 A24  Yes  Yes B+ 
   41–50 (B17–B26) LVCGERGFFY 106631 A1  Yes  Yes B+ 
   41–50 (B17–B26) LVCGERGFFY 106631 A3  Yes  Yes B+ 
   41–50 (B17–B26) LVCGERGFFY 106631 A11  Yes  Yes B+ 
   42–51 (B18–B27) VCGERGFFYT 102877 A1  Yes  Yes B+ 
   42–51 (B18–B27) VCGERGFFYT 102877 A*02:01  Yes Yes Yes B+ 
   42–51 (B18–B27) VCGERGFFYT 102877 B8  Yes  Yes B+ 
   42–51 (B18–B27) VCGERGFFYT 102877 B18  Yes  Yes B+ 
   44–51 (B20–B27) GERGFFYT 105816 A1  Yes  Yes B+ 
   44–51 (B20–B27) GERGFFYT 105816 B8  Yes  Yes B+ 
   45–53 (B21–B29) ERGFFYTPK 106399 A3  Yes  Yes B+ 
   49–57 (B25–C1) FYTPKTRRE 105799 B8  Yes  Yes B+ 
   51–61 (B27–C5) TPKTRREAEDL 106918 B8  Yes  Yes B+ 
   76–84 (C20–C28) SLQPLALEG 101242 A*02:01  Yes Yes Yes A– 
   76–84 (C20–C28) SLQPLALEG 101242 A3  Yes  Yes B+ 
   79–88 (C23–C32) PLALEGSLQK 159292 A3  Yes  Yes B+ 
   81–89 (C25–C33) ALEGSLQKR 104727 A*02:01   Yes Yes 
   85–94 (C29–A5) SLQKRGIVEQ 101241 A*02:01  Yes Yes Yes A– 
   90–99 (A1–A10) GIVEQCCTSI 100882 A*02:01  Yes Yes Yes A– 
   101–109 (A12–A20) SLYQLENYC 101248 A*02:01  Yes Yes Yes A– 
ISL-1 (ISL1276–284 GLQANPVEV 952138 A*02:01 Yes Yes  Yes 
KCNK16 (KCNK16129–137 ALLGIPLNV 952014 A*02:01  Yes  Yes B+ 
KIF1A (KIF1A1347–1355 VLDTSVAYV 779283 A*02:01  Yes  Yes B+ 
PC2 (PCSK230–38 FTNHFLVEL 952113 A*02:01  Yes  Yes B+ 
S100β (S100B10–18 ALIDVFHQY 562065 A*02:01  Yes Yes Yes B+ 
   20–28 GREGDKHKL 910732 A*02:01  Yes Yes Yes B+ 
SCG5 (SCG5186–195 YLQGQRLDNV 952620 A*02:01  Yes  Yes B+ 
UCN3 (UCN31–9 MLMPVHFLL 952274 A*02:01 Yes Yes  Yes 
VTDB (GC211–219 LLTTLSNRV 767640 A*02:01  Yes Yes  D+ 
   235–243 NLIKLAQV 767652 A*02:01  Yes Yes  D+ 
ZnT8 (SLC30A816–24 KMYAFTLES 171844 A*02:01  Yes Yes Yes B+ 
   16–25 KMYAFTLESV 504008 A*02:01  Yes   D+ 
   93–101 HIAGSLAVV 168764 A2  Yes Yes Yes B+ 
   107–115 LLIDLTSFL 169149 A*02:01  Yes Yes  C– 
   107–116 LLIDLTSFLL 504015 A*02:01  Yes Yes Yes B+ 
   110–118 DLTSFLLSL 168356 A*02:01  Yes   D+ 
   114–123 FLLSLFSLWL 168578 A*02:01  Yes Yes Yes B+ 
   115–123 LLSLFSLWL 172188 A*02:01  Yes Yes Yes A– 
   140–148 EILGALLSI 168356 A*02:01  Yes   D+ 
   141–149 ILGALLSIL 168867 A*02:01  Yes   D+ 
   145–153 LLSILCIWV 172186 A*02:01   Yes  
   153–161 VVTGVLVYL 170038 A*02:01  Yes Yes Yes B+ 
   165–173 RLLYPDYQI 173061 A*02:01  Yes Yes Yes B+ 
   173–181 IQATVMIIV 171556 A*02:01  Yes Yes Yes B+ 
   177–186 VMIIVSSLAV 504065 A*02:01  Yes Yes Yes B+ 
   185–194 AVAANIVLTV 168235 A*02:01  Yes Yes Yes A– 
   186–194 VAANIVLTV 173562 A*02:01 Yes Yes Yes Yes A+ 
   200–208 CLGHNHKEV 503971 A*02:01  Yes   D+ 
   221–229 ALGDLFQSI 168159 A*02:01  Yes Yes Yes B+ 
   228–236 SISVLISAL 169725 A2  Yes Yes Yes B+ 
   245–254 KIADPICTFI 504005 A*02:01  Yes   D+ 
   253–261 FIFSILVLA 171037 A*02:01  Yes Yes Yes B+ 
   253–261 FIF(S→pS)ILVLA 437274 A2  Yes     C– 
   257–266 ILVLASTITI 168881 A2  Yes Yes Yes B+ 
   266–274 ILKDFSILL 168874 A*02:01  Yes Yes Yes B+ 
   273–282 LLMEGVPKSL 169153 A*02:01  Yes   D+ 
   280–288 KSLNYSGVK 171933 A*02:01  Yes Yes Yes B+ 
   281–290 SLNYSGVKEL 169744 A*02:01  Yes   D+ 
   291–300 ILAVDGVLSV 168865 A*02:01  Yes Yes Yes B+ 
   292–300 LAVDGVLSV 172015 A*02:01  Yes   D+ 
   299–308 SVHSLHIWSL 169790 A*02:01  Yes   D+ 
   314–322 ILSAHVATA 168880 A*02:01  Yes   D+ 
   343–351 TMHSLTIQM 173491 A*02:01  Yes Yes Yes B+ 
Nonconventional epitopes, excluding posttranslational modifications, which are included above
Epitope sourcefPositionSequenceIEDB#aMHCHuman islets, pLNsbHuman blood, spleenbHLA-Tg mousebNPPcEvidencedReporting articlese
CCNI-008 14–22 KLNWDLHTA 952207 A*02:01  Yes   D+ 
GAD2-003 179–187 KIIKLFFRL 952200 A*02:01  Yes   D+ 
GNAS-036 67–75 YMCTHRLLL 952623 A*02:01  Yes   D+ 
  124–132 AMSNLVPPV 952026 A*02:01  Yes   D+ 
IAPP-002 33–42 VLSRNILLEL 952582 A*02:01  Yes   D+ 
IAPP hybrid 15–17/5–10 VALKLQVFL 952568 A*02:01 Yes Yes  Yes 
INS-DRiP 1–9 MLYQHLLPL 606356 A*02:01  Yes   C– 
PTPRN-021 392–402 SLAAGVKLLEI 952381 A*02:01  Yes   D+ 
  398–407 KLLEILAEHV 952204 A*02:01  Yes   D+ 
PTPRN2-005 11–19 LLLLLPPRV 101025 A*02:01  Yes   D+ 
  19–27 VLPAAPSSV 952581 A*02:01  Yes   D+ 
REXO2-020 2–10 SVANALWIV 952401 A*02:01  Yes   D+ 
SCG5-009 186–194 FLSGAVNRL 952103 A*02:01 Yes Yes  Yes 
SLC30A8-002 16–25 KMYAFTLESV 504008 A*02:01  Yes   D+ 
Nonconventional epitopes, excluding posttranslational modifications, which are included above
Epitope sourcefPositionSequenceIEDB#aMHCHuman islets, pLNsbHuman blood, spleenbHLA-Tg mousebNPPcEvidencedReporting articlese
CCNI-008 14–22 KLNWDLHTA 952207 A*02:01  Yes   D+ 
GAD2-003 179–187 KIIKLFFRL 952200 A*02:01  Yes   D+ 
GNAS-036 67–75 YMCTHRLLL 952623 A*02:01  Yes   D+ 
  124–132 AMSNLVPPV 952026 A*02:01  Yes   D+ 
IAPP-002 33–42 VLSRNILLEL 952582 A*02:01  Yes   D+ 
IAPP hybrid 15–17/5–10 VALKLQVFL 952568 A*02:01 Yes Yes  Yes 
INS-DRiP 1–9 MLYQHLLPL 606356 A*02:01  Yes   C– 
PTPRN-021 392–402 SLAAGVKLLEI 952381 A*02:01  Yes   D+ 
  398–407 KLLEILAEHV 952204 A*02:01  Yes   D+ 
PTPRN2-005 11–19 LLLLLPPRV 101025 A*02:01  Yes   D+ 
  19–27 VLPAAPSSV 952581 A*02:01  Yes   D+ 
REXO2-020 2–10 SVANALWIV 952401 A*02:01  Yes   D+ 
SCG5-009 186–194 FLSGAVNRL 952103 A*02:01 Yes Yes  Yes 
SLC30A8-002 16–25 KMYAFTLESV 504008 A*02:01  Yes   D+ 
a

IEDB identifier (www.iedb.org).

b

Yes, T-cell responses observed using the indicated T-cell sources. See Supplementary Table 1 for details.

c

NPP, natural processing/presentation; yes, evidence is available. See Supplementary Table 1 for details.

d

See Fig. 2 for epitope scoring criteria.

e

See Supplementary Table 1 for details.

f

Gene names followed by a hyphen and three numbers refer to splice variants derived from the indicated genes. DRiP, defective ribosomal product.

Table 2

CD4+ T-cell epitopes in type 1 diabetes

Antigen (gene)PositionSequenceIEDB#aMHCHuman islets, pLNsbHuman blood, spleenbHLA-Tg mousebNPPcEvidencedReporting articlese
CHGA (CHGA) 342–355 WSKMDQLAKELTAE 226405 DQ8  Yes  Yes B+ 
DMK (DMPK) 9–28 RLQQLVLDPGFLGLEPLLDL 138808 DR0401  Yes   C– 
GAD65 (GAD21–20 MASPGSGFWSFGSEDGSGDS 101054 Class II  Yes   D+ 
   1–20 MASPGSGFWSFGSEDGSGDS 101054 DR0401  Yes   C– 
   47–66 LLYGDAEKPAESGGSQPPRA 105302 Class II  Yes   D+ 
   73–92 CACDQKPCSCSKVDVNYAFL 142554 DR  Yes   C– 
   73–92 CACDQKPCSCSKVDVNYAFL 142554 DR0401  Yes   C– 
   81–100 SCSKVDVNYAFLHATDLLPA 104234 DR  Yes   C– 
   86–103 DVNYAFLHATDLLPACDG 186992 DR4  Yes   D+ 
   88–99 NYAFLHATDLLP 104163 DR0101  Yes  Yes A– 
   88–99 NYAFLHATDLLP 104163 DRB5  Yes   C– 
   89–108 YAFLHATDLLPACDGE(R→Cit)PTL 230433 DR0401  Yes   C– 
   101–115 CDGERPTLAFLQDVM 6101 DQ  Yes   D+ 
   105–124 RPTLAFLQDVMNILLQYVVK 143044 DR0401  Yes   C– 
   108–129 LAFLQDVMNILLQYVVKSFDRS 105275 Class II  Yes   D+ 
   113–132 DVMNILLQYVVKSFDRSTKV 138762 DR0401  Yes  Yes A– 
   113–132 DVMNILLQYVVKSFDRSTKV 138762 DR  Yes   C– 
   113–132 DVMNILLQYVVKSFDRSTKV 138762 DRB4  Yes   D+ 
   115–127 MNILLQYVVKSFD 100311 DR0401 Yes  Yes Yes A+ 
   115–127 MNILLQYVVKSFD 100311 Class II  Yes   D+ 
   115–127 MNILL(Q→E)YVVKSFD 230399 DR0401  Yes   C– 
   115–130 MNILLQYVVKSFDRST 104903 DR0401   Yes Yes 
   116–129 NILLQYVVKSFDRS 102675 DRB4  Yes   C– 
   116–127 NILLQYVVKSFD 104150 DRB4  Yes   C– 
   121–140 YVVKSFDRSTKVIDFHYPNE 102974 DQ8  Yes Yes Yes A– 
   126–140 FDRSTKVIDFHYPNE 103164 DQ  Yes   D+ 
   146–165 NWELADQPQNLEEILMHCQT 103455 DR1601  Yes  Yes A– 
   153–172 P(Q→E)NLEEILMHC(Q→E)TTLKYAIK 230405 DR0401  Yes   C– 
   157–176 EEILMHCQTTLKYAIKTGHP 105161 Class II  Yes   D+ 
   172–191 KTGHPRYFNQLSTGLDMVGL 105271 Class II  Yes   D+ 
   173–187 TGHPRYFNQLSTGLD 104649 Class II  Yes   D+ 
   174–185 GHPRYFNQLSTG 103219 DR0401  Yes  Yes A– 
   175–190 HPRYFNQLSTGLDMVG 187007 DR4  Yes   D+ 
   177–196 RYFNQLSTGLDMVGLAADWL 143056 DR  Yes   C– 
   200–217 ANTNMFTYEIAPVFVLLE 103808 DR8 or DR9  Yes   C– 
   201–220 NTNMFTYEIAPVFVLLEYVT 102698 DQ8   Yes Yes B– 
   201–220 NTNMFTYEIAPVFVLLEYVT 102698 DR0401  Yes  Yes A– 
   202–221 TNMFTYEIAPVFVLLEYVTL 105004 Class II  Yes   D+ 
   203–226 NMFTYEIAPVFVLLEYVTLKKMRE 187017 DR4  Yes   D+ 
   206–220 TYEIAPVFVLLEYVT 67328 DQ  Yes   D+ 
   209–228 IAPVFVLLEYVTLKKMREII 142728 DRB4  Yes   D+ 
   217–236 EYVTLKKMREIIGWPGGSGD 104481 DR  Yes   C– 
   225–244 REIIGWPGGSGDGIFSPGGA 143023 DR  Yes   C– 
   231–250 PGGSGDGIFSPGGAISNMYA 102715 DQ8   Yes Yes B– 
   232–251 GGSGDGIFSPGGAISNMYAM 105216 Class II  Yes   D+ 
   243–267 GAISNMYAMMIARFKMFPEVKEKGM 186999 DR4  Yes   D+ 
   247–266 NMYAMMIARFKMFPEVKEKG 45043 DR3  Yes   C– 
   247–266 NMYAMMIARFKMFPEVKEKG 45043 Class II  Yes   C– 
   247–279 NMYAMMIARFKMFPEVKEKGMAALPRLIAFTSE 101931 Class II  Yes   D+ 
   248–257 MYAMMIARFK 104140 DRB5  Yes  Yes A– 
   248–259 MYAMMIARFKMF 104141 DR0101  Yes  Yes A– 
   249–268 YAMMIARFKMFPEVKEKGMA 143224 DR  Yes   C– 
   250–266 AMMIARFKMFPEVKEKG 234479 DQ8  Yes   C– 
   251–270 MMIARFKMFPEVKEKGMAAL 104118 DR12  Yes   C– 
   252–266 MIARFKMFPEVKEKG 104114 DR0404  Yes   C– 
   252–266 MIARFKMFPEVKEKG 104114 Class II  Yes   D+ 
   254–276 ARFKMFPEVKEKGMAALPRLIAF 118749 Class II  Yes   D+ 
   260–279 PEVKEKGMAALPRLIAFTSE 105471 Class II  Yes   D+ 
   261–275 EVKEKGMAALPRLIA 186666 Class II  Yes   D+ 
   261–280 EVKEKGMAALPRLIAFTSEH 103893 DQ8  Yes   C– 
   264–287 EKGMAALPRLIAFTSEHSHFSLKK 186995 DR4  Yes   D+ 
   265–284 KGMAALPRLIAFTSEHSHFS 142811 DR0401  Yes  Yes A– 
   265–284 KGMAALP(R→Cit)LIAFTSEHSHFS 230391 DR0401  Yes   C– 
   265–284 KGMAALPRLIAFTSEHSHFS 142811 DR  Yes   C– 
   266–285 GMAALPRLIAFTSEHSHFSL 104502 DR0401  Yes   D+ 
   270–283 LPRLIAFTSEHSHF 103379 DR0401  Yes  Yes A– 
   270–284 LPRLIAFTSEHSHFS 103380 DRB4  Yes  Yes A– 
   270–287 LPRLIAFTSEHSHFSLKK 157610 DR0401  Yes   D+ 
   271–285 PRLIAFTSEHSHFSL 104934 DR0401   Yes Yes 
   272–283 RLIAFTSEHSHF 103556 DRB4  Yes  Yes A– 
   273–292 LIAFTSEHSHFSLKKGAAAL 138782 DR0401  Yes  Yes A– 
   273–292 LIAFTSEHSHFSLKKGAAAL 138782 DR  Yes   C– 
   274–286 IAFTSEHSHFSLK 25275 DR0401 Yes Yes Yes Yes A+ 
   274–286 IAFTSEHSHFSLK 25275 Class II  Yes   D+ 
   276–284 FTSEHSHFS 231904 DR0404  Yes   C– 
   289–303 AAALGIGTDSVILIK 130713 Class II  Yes   D+ 
   290–309 AALGIGTDSVILIKCDERGK 104403 Class II  Yes   D+ 
   297–316 DSVILIKCDERGKMIPSDLE 142591 DR0401  Yes   C– 
   305–324 DERGKMIPSDLERRILEAKQ 105133 DR0401  Yes  Yes A– 
   320–339 LEAKQKGFVPFLVSATAGTT 105281 Class II  Yes   D+ 
   321–340 EAKQKGFVPFLVSATAGTTV 103867 DR0401  Yes  Yes A– 
   335–352 TAGTTVYGAFDPLLAVAD 226392 DR3  Yes   D+ 
   338–352 TTVYGAFDPLLAVAD 187030 DR4  Yes   D+ 
   353–372 ICKKYKIWMHVDAAWGGGLL 142730 Class II  Yes   C– 
   353–372 ICKKYKIWMHVDAAWGGGLL 142730 DRB4  Yes   D+ 
   354–372 CKKYKIWMHVDAAWGGGLL 186990 DR4  Yes   D+ 
   356–370 KYKIWMHVDAAWGGG 104868 DR0401   Yes Yes 
   368–388 GGGLLMSRKHKWKLSGVERAN 103921 DPw2  Yes   C– 
   369–388 GGLLMSRKHKWKLSGVERAN 142674 DR  Yes   C– 
   369–392 GGLLMSRKHKWKLSGVERANSVTW 187001 DR4  Yes   D+ 
   376–390 KHKWKLSGVERANSV 104852 DR0401   Yes Yes 
   377–396 HKWKLSGVERANSVTWNPHK 142717 DR0401  Yes   C– 
   377–396 HKWKLSGVERANSVTWNPHK 142717 DR  Yes   C– 
   385–404 ERANSVTWNPHKMMGVPLQC 105169 Class II  Yes   D+ 
   405–424 SALLVREEGLMQNCNQMHAS 187026 DR4  Yes   D+ 
   413–431 GLMQNCNQMHASYLFQQDK 103939 DR0101  Yes   C– 
   416–435 QNCNQMHASYLFQQDKHYDL 105488 Class II  Yes   D+ 
   431–445 KHYDLSYDTGDKALQ 103306 DQ  Yes   D+ 
   433–452 YDLSYDTGDKALQCGRHVDV 143226 DR0401  Yes  Yes A– 
   433–452 YDLSYDTGDKALQCGRHVDV 143226 Class II  Yes   C– 
   446–466 CGRHVDVFKLWLMWRAKGTTG 105120 Class II  Yes   D+ 
   450–470 VDVFKLWLMWRAKGTTGFEAH 187032 DR4  Yes   D+ 
   461–473 AKGTTGFEAHVDK 103035 DQ  Yes   D+ 
   462–483 KGTTGFEAHVDKCLELAEYLYN 105261 Class II  Yes   D+ 
   471–490 VDKCLELAEYLYNIIKNREG 102882 DQ8   Yes Yes B– 
   473–492 KCLELAEYLYNIIKNREGYE 142807 DR0401  Yes  Yes A– 
   479–498 EYLYNIIKNREGYEMVFDGK 105173 Class II  Yes   D+ 
   480–496 YLYNIIKNREGYEMVFD 187035 DR4  Yes   D+ 
   481–495 LYNIIKNREGYEMVF 104898 DR0401   Yes Yes 
   491–510 YEMVFDGKPQHTNVCFWYIP 104352 DR3  Yes   C– 
   491–510 YEMVFDGKPQHTNVCFWYIP 104352 DQ5  Yes   C– 
   493–507 MVFDGKPQHTNVCFW 104575 Class II  Yes   D+ 
   494–513 VFDGKPQHTNVCFWYIPPSL 119539 Class II  Yes   D+ 
   501–520 HTNVCFWYIPPSLRTLEDNE 103978 DR1  Yes   C– 
   501–520 HTNVCFWYIPPSLRTLEDNE 103978 DR4  Yes   C– 
   504–518 VCFWYIPPSLRTLED 187031 DR4  Yes   D+ 
   505–519 CFWYIPPSLRTLEDN 101509 Class II  Yes   C– 
   505–519 CFWYIPPSLRTLEDN 101509 DQ8  Yes   D+ 
   506–518 FWYIPPSLRTLED 103913 Class II  Yes   D+ 
   509–528 IPPSLRTLEDNEERMSRLSK 102537 Class II  Yes   D+ 
   511–525 PSLRTLEDNEERMSR 104602 DR0401   Yes Yes 
   511–525 PSLRTLEDNEERMSR 104602 DR4  Yes   D+ 
   511–530 PSLRTLEDNEERMSRLSKVA 104189 DR3  Yes   C– 
   521–535 ERMSRLSKVAPVIKA 101609 Class II  Yes   C– 
   521–535 ERMSRLSKVAPVIKA 101609 DQ8  Yes   D+ 
   524–543 SRLSKVAPVIKARMMEYGTT 102085 Class II  Yes   D+ 
   529–548 VAPVIKARMMEYGTTMVSYQ 143155 DRB4  Yes   D+ 
   533–547 IKARMMEYGTTMVSY 104522 Class II  Yes   D+ 
   536–550 RMMEYGTTMVSYQPL 103560 DQ  Yes   D+ 
   536–550 RMMEYGTTMVSYQPL 103560 DQ8   Yes  D– 
   539–558 EYGTTMVSYQPLGDKVNFFR 105172 Class II  Yes   D+ 
   545–564 VSYQPLGDKVNFFRMVISNP 143204 DR0401  Yes  Yes A– 
   545–585 VSYQPLGDKVNFFRMVISNPAATHQDIDFLIEEIERLGQDL 102216 Class II  Yes   D+ 
   546–560 SYQPLGDKVNFFRMV 104994 DR0401   Yes Yes 
   550–570 LGDKVNFFRMVISNPAATHQD 187013 DR4  Yes   D+ 
   551–565 GDKVNFFRMVISNPA 104792 DR0401   Yes Yes 
   552–572 DKVNFFRMVISNPAATHQDID 119442 DR0401  Yes   C– 
   553–570 KVNFFRMVISNPAATHQD 102589 DR4  Yes  Yes A– 
   553–572 KVNFFRMVISNPAATHQDID 138779 DR0401  Yes  Yes A– 
   553–572 KVNFFRMVISNPAATHQDID 138779 Class II  Yes   C– 
   553–572 KVNFFRMVISNPAATHQDID 138779 DRB4  Yes   D+ 
   553–572 KVNFF(R→Cit)MVISNPAATHQDID 230397 DR0401  Yes   C– 
   554–573 VNFFRMVISNPAATHQDIDF 119541 Class II  Yes   D+ 
   554–567 VNFFRMVISNPAAT 158453 DR0401  Yes   D+ 
   554–575 VNFFRMVISNPAATHQDIDFLI 226402 DR4  Yes   D+ 
   555–567 NFFRMVISNPAAT 101067 DR0401 Yes Yes   C+ 
   555–567 NFFRMVISNPAAT 101067 DR0404  Yes   C– 
   555–567 NFFRMVISNPAAT 101067 DR4  Yes   D+ 
   556–570 FFRMVISNPAATHQD 104775 DR0401   Yes Yes 
   556–575 FFRMVISNPAATHQDIDFLI 103167 DR0401  Yes  Yes A– 
   563–575 NPAATHQDIDFLI 102684 DRB4  Yes  Yes A– 
   565–580 AATHQDIDFLIEEIER 104721 DR0401   Yes Yes 
   566–585 ATHQDIDFLIEEIERLGQDL 103818 Class II  Yes   D+ 
   566–585 ATHQDIDFLIEEIERLGQDL 103818 DRB4  Yes   D+ 
GRP78 (HSPA5195–209 VMRIINEPTAAAIAY 546164 DR0401  Yes   D+ 
   195–209 VM(R→Cit)IINEPTAAAIAY 858100 DR0401  Yes   D+ 
   292–305 VEKAK(R→Cit)ALSSQHQA 590605 Class II Yes    C+ 
   498–512 EVTFEIDVNGILRVT 857879 DR0401  Yes   D+ 
   498–512 EVTFEIDVNGIL(R→Cit)VT 857878 DR0401  Yes   C– 
   500–514 TFEIDVNGIL(R→Cit)VTAE 858056 DR0401  Yes   D+ 
HSP60 (HSPD131–50 KFGADARALMLQGVDLLADA 79582 Class II  Yes   D+ 
   136–155 NPVEIRRGVMLAVDAVIAEL 102687 Class II  Yes   D+ 
   242–256 AYVLLSEKKISSIQS 114753 DR  Yes   D+ 
   255–275 QSIVPALEIANAHRKPLVIIA 102750 Class II  Yes   D+ 
   280–294 GEALSTLVLNRLKVG 114829 DR  Yes   D+ 
   286–305 LVLNRLKVGLQVVAVKAPGF 40453 Class II  Yes   D+ 
   394–408 LAKLSDGVAVLKVGG 104547 Class II  Yes   D+ 
   436–455 IVLGGGCALLRCIPALDSLT 79579 Class II  Yes   D+ 
   466–485 EIIKRTLKIPAMTIAKNAGV 79540 Class II  Yes   D+ 
   511–530 VNMVEKGIIDPTKVVRTALL 102911 Class II  Yes   D+ 
HSP70 (HSPA1B1–20 MAKAAA(I→V)GIDLGTTYSCVGV 102642 Class II  Yes   D+ 
   166–185 GLNVLRIINEPTAAAIAYGL 102794 Class II  Yes   D+ 
   211–230 TIDDGIFEVKATAGDTHLGG 102846 Class II  Yes   D+ 
   226–245 THLGGEDFDNRLVNHFVEEF 102842 Class II  Yes   D+ 
   271–290 KRTLSSSTQASLEIDSLFEG 102579 Class II  Yes   D+ 
   391–410 LLLLDVAPLSLGLETAGGVM 102619 Class II  Yes   D+ 
   421–440 PTKQTQIFTTYSDNQPGVLI 102728 Class II  Yes   D+ 
   497–516 KANKITITNDKGRLSKEEIE 102548 Class II  Yes   D+ 
   512–531 KEEIERMVQEAEKYKAEDEV 102553 Class II  Yes   D+ 
IA-2 (PTPRN142–159 LQDIPTGSAPAAQHRLPQ 536828 DQ8 or DQ8-trans  Yes  Yes B+ 
   197–209 PSLSYEPALLQPY 104603 Class II  Yes   D+ 
   198–216 SLSYEPALL(Q→E)PYLFH(Q→E)FGS 914422 DQ8 Yes Yes   C+ 
   264–284 LPGPSPAQLFQDSGLLYLAQE 534743 DR4  Yes  Yes B+ 
   293–311 VPRLPEQGSSSRAEDSPEG 538314 DQ  Yes  Yes B+ 
   318–333 GDRGEKPASPAVQPDA 535895 DQ  Yes  Yes B+ 
   319–342 DRGEKPASPAVQPDAALQRLAAVL 534686 DR3  Yes  Yes B+ 
   449–488 SPLGQSQPTVAGQPSARPAAEEYGYIVTDQKPLSLAAGVK 534789 DR3  Yes  Yes B+ 
   467–482 AAEEYGYIVTD(Q→E)KPLS 914337 DQ8  Yes   C– 
   490–502 LEILAEHVHMSSG 104552 Class II  Yes   D+ 
   502–514 GSFINISVVGPAL 104510 Class II  Yes   D+ 
   523–536 QNLSLADVT(Q→E)(Q→E)AGL 914404 DQ8  Yes   C– 
   545–562 TGL(Q→E)IL(Q→E)TGVG(Q→E)REEAAA 914426 Class II Yes    C+ 
   545–562 TGL(Q→E)IL(Q→E)TGVG(Q→E)REEAAA 914426 DQ8 Yes Yes   C+ 
   575–587 RSVLLTLVALAGV 104618 Class II  Yes   D+ 
   601–618 RQHARQQDKERLAALGPE 104966 DQ8   Yes  D– 
   608–620 DKERLAALGPEGA 910445 Class II  Yes   D+ 
   616–633 GPEGAHGDTTFEYQDLCR 104813 DQ8   Yes  D– 
   646–663 EGPPEPSRVSSVSSQFSD 104764 DQ8   Yes  D– 
   654–674 VSSVSSQFSDAAQASPSSHSS 933295 DR4  Yes  Yes B+ 
   657–674 VSSQFSDAAQASPSSHSS 104677 DR0401  Yes   D+ 
   661–678 FSDAAQASPSSHSSTPSW 104781 DQ8   Yes  D– 
   685–700 ANMDISTGHMILAYME 105676 DR4  Yes   D+ 
   709–731 LAKEWQALCAYQAEPNTCATAQG 104546 DR0401  Yes  Yes B+ 
   709–733 LAKEWQALCAYQAEPNTCATAQGEG 874656 DR0401  Yes   D+ 
   709–736 LAKEWQALCAYQAEPNTCATAQGEGNIK 134126 Class II  Yes   D+ 
   713–728 WQALCAYQAEPNTCAT 106189 DR4  Yes   D+ 
   717–729 CAYQAEPNTCATA 104437 Class II  Yes   D+ 
   721–738 AEPNTCATAQGEGNIKKN 104723 DQ8   Yes  D– 
   745–760 PYDHARIKLKVESSPS 106021 DR4  Yes   D+ 
   751–770 IKLKVESSPSRSDYINASPI 104523 DR0401  Yes   C– 
   752–775 KLKVESSPSRSDYINASPIIEHDP 134118 Class II  Yes   D+ 
   752–775 KLKVESSPSRSDYINASPIIEHDP 134118 DR4  Yes  Yes B+ 
   766–783 NASPIIEHDPRMPAYIAT 104909 DQ8   Yes  D– 
   778–790 PAYIATQGPLSHT 104590 Class II  Yes   D+ 
   787–802 LSHTIADFWQMVWESG 105943 DR4  Yes   D+ 
   793–808 DFWQMVWESGCTVIVM 105709 DR4  Yes   D+ 
   793–817 DFWQMVWESGCTVIVMLTPLVEDGV 233467 Class II  Yes   D+ 
   797–809 MVWESGCTVIVML 910496 Class II  Yes   D+ 
   797–817 MVWESGCTVIVMLTPLVEDGV 104578 DR0401  Yes   D+ 
   799–814 WESGCTVIVMLTPLVE 106184 DR3-DQ2  Yes   D+ 
   799–814 WESGCTVIVMLTPLVE 106184 DR4  Yes   D+ 
   803–815 CTVIVMLTPLVED 104441 Class II  Yes   D+ 
   804–816 TVIVMLTPLVEDG 910528 Class II  Yes   D+ 
   805–817 VIVMLTPLVEDGV 133730 Class II  Yes   C– 
   805–820 VIVMLTPLVEDGVKQC 106162 DR3-DQ2  Yes   D+ 
   805–820 VIVMLTPLVEDGVKQC 106162 DR4  Yes   D+ 
   826–843 DEGASLYHVYEVNLVSEH 922741 DQ8   Yes  D– 
   830–842 SLYHVYEVNLVSE 104629 Class II  Yes   D+ 
   831–850 LYHVYEVNLVSEHIWCEDFL 104566 DP0401  Yes   C– 
   841–856 SEHIWCEDFLVRSFYL 106100 DR3-DQ2  Yes   D+ 
   841–856 SEHIWCEDFLVRSFYL 106100 DR4  Yes   D+ 
   841–860 SEHIWCEDFLVRSFYLKNVQ 104620 DP0401  Yes   C– 
   841–860 SEHIWCEDFLVRSFYLKNVQ 104620 DR4  Yes   D+ 
   845–860 WCEDFLVRSFYLKNVQ 106182 DR4  Yes   D+ 
   847–862 EDFLVRSFYLKNVQTQ 105741 DR3-DQ2  Yes   D+ 
   847–862 EDFLVRSFYLKNVQTQ 105741 DR4  Yes   D+ 
   853–872 SFYLKNVQTQETRTLTQFHF 134229 DR4  Yes   D+ 
   854–866 FYLKNVQTQETRT 910467 Class II  Yes   D+ 
   854–872 FYLKNVQTQETRTLTQFHF 104493 DR0401  Yes   D+ 
   889–904 DFRRKVNKCYRGRSCP 105708 DR4-DQ8  Yes   D+ 
   918–930 TYILIDMVLNRMA 104662 Class II  Yes   D+ 
   919–934 YILIDMVLNRMAKGVK 106198 DR3-DQ2  Yes   D+ 
   919–934 YILIDMVLNRMAKGVK 106198 DR4  Yes   D+ 
   931–948 KGVKEIDIAATLEHVRDQ 922742 DQ8   Yes  D– 
   933–945 VKEIDIAATLEHV 910531 Class II  Yes   D+ 
   955–975 SKDQFEFALTAVAEEVNAILK 104626 DR0401  Yes   D+ 
   957–969 DQFEFALTAVAEE 104447 Class II  Yes   D+ 
   959–974 FEFALTAVAEEVNAIL 105774 DR4  Yes   D+ 
   961–979 FALTAVAEEVNAILKALPQ 104772 DQ8   Yes  D– 
IAPP (IAPP65–84 VGSNTYGK(R→Cit)NAVEVLK(R→Cit)EPL 590688 Class II Yes    C+ 
   65–84 VGSNTYGK(R→Cit)NAVEVLK(R→Cit)EPL 590688 DQ8  Yes   C– 
ICA69 (ICA136–47 AFIKATGKKEDE 104413 Class II  Yes   D+ 
IGRP (G6PC213–25 QHLQKDYRAYYTF 106039 DR0301  Yes   C– 
   17–36 KDYRAYYTFLNFMSNVGDPR 138777 DR0401  Yes   D+ 
   23–35 YTFLNFMSNVGDP 106206 DR0401  Yes   C– 
   177–196 HQVILGVIGGMLVAEAFEHT 644404 Class II  Yes   C– 
   226–238 RVLNIDLLWSVPI 106096 DR0301  Yes   C– 
   241–260 KWCANPDWIHIDTTPFAGLV 138780 DR0401  Yes   D+ 
   241–260 KWCANPDWIHIDTTPFAGLV 138780 Class II  Yes   C– 
   247–259 DWIHIDTTPFAGL 105736 DR0401  Yes   C– 
   305–324 QLYHFLQIPTHEEHLFYVLS 648592 DR  Yes   C– 
INS (INS1–15 (L1–L15) MALWMRLLPLLALLA 840899 DQ8   Yes Yes B– 
   1–16 (L1–L16) MALWMRLLPLLALLAL 103406 Class II  Yes   D+ 
   1–24 (L1–L24) MALWMRLLPLLALLALWGPDPAAA 105962 DQ8   Yes  D– 
   1–24 (L1–L24) MALWMRLLPLLALLALWGPDPAAA 105962 DQ6   Yes  D– 
   5–20 (L5–L20) MRLLPLLALLALWGPD 923548 Class II  Yes   D+ 
   8–23 (L8–L23) LPLLALLALWGPDPAA 840893 DQ8   Yes Yes B– 
   9–24 (L9–L24) PLLALLALWGPDPAAA 923645 Class II  Yes   D+ 
   9–28 (L9–B4) PLLALLALWGPDPAAAFVNQ 142953 DRB4  Yes   D+ 
   11–26 (L11–B2) LALLALWGPDPAAAFV 104548 DR0401   Yes Yes B– 
   13–28 (L13–B4) LLALWGPDPAAAFVNQ 923488 Class II  Yes   D+ 
   14–33 (L14–B9) LALWGPDPAAAFVNQHLCGS 105917 DQ8   Yes  D– 
   14–33 (L14–B9) LALWGPDPAAAFVNQHLCGS 105917 DQ6   Yes  D– 
   16–30 (L16–B6) LWGPDPAAAFVNQHL 933452 DQ8   Yes Yes B– 
   17–24 (L17–24) WGPDPAAA 103728 DQ8-trans  Yes  Yes B+ 
   17–32 (L17–B8) WGPDPAAAFVNQHLCG 923967 Class II  Yes   D+ 
   18–30 (L18–B6) GPDPAAAFVNQHL 933381 DQ8   Yes Yes B– 
   20–35 (L20–B11) DPAAAFVNQHLCGSHL 840818 DQ8   Yes Yes B– 
   21–36 (L21–B12) PAAAFVNQHLCGSHLV 104589 DR0401   Yes Yes B– 
   21–36 (L21–B12) PAAAFVNQHLCGSHLV 104589 Class II  Yes   D+ 
   25–40 (B1–B16) FVNQHLCGSHLVEALY 840840 Class II  Yes   D+ 
   25–40 (B1–B16) FVNQHLCGSHLVEALY 840840 DQ8   Yes Yes B– 
   25–41 (B1–B17) FVNQHLCGSHLVEALYL 103908 Class II  Yes   D+ 
   30–46 (B6–B22) LCGSHLVEALYLVCGER 104030 Class II  Yes   D+ 
   30–46 (B6–B22) LCGSHLVEALYLVCGER 104030 DQ8  Yes   C– 
   31–47 (B7–B23) CGSHLVEALYLVCGERG 933280 Class II  Yes   D+ 
   33–47 (B9–B23) SHLVEALYLVCGERG 58388 DQ8-trans Yes    C+ 
   33–47 (B9–B23) SHLVEALYLVCGERG 58388 DQ8 Yes Yes Yes Yes A+ 
   34–49 (B10–B25) HLVEALYLVCGERGFF 102517 Class II  Yes   C– 
   34–53 (B10–B29) HLVEALYLVCGERGFFYTPK 105241 DQ8   Yes  D– 
   34–53 (B10–B29) HLVEALYLVCGERGFFYTPK 105241 DQ6   Yes  D– 
   35–47 (B11–B23) LVEALYLVCGERG 104895 DQ8  Yes   C– 
   35–49 (B11–B25) LVEALYLVCGERGFF 104062 DQ8 Yes    C+ 
   35–51 (B11–B27) LVEALYLVCGERGFFYT 103394 DR1601  Yes   C– 
   35–51 (B11–B27) LVEALYLVCGERGFFYT 103394 Class II  Yes   D+ 
   37–47 (B13–B23) EALYLVCGERG 104759 DQ8  Yes   D+ 
   38–54 (B14–B30) ALYLVCGERGFFYTPKT 933279 Class II  Yes   D+ 
   40–55 (B16–B31) YLVCGERGFFYTPKTR 840972 DQ8   Yes Yes B– 
   40–56 (B16–B32) YLVCGERGFFYTPKTRR 923983 Class II  Yes   D+ 
   42–71 (B18–C15) VCGERGFFYTPKTRREAEDLQVGQVELGGG 105563 Class II  Yes   D+ 
   44–60 (B20–C4) GERGFFYTPKTRREAED 103917 Class II  Yes   D+ 
   44–63 (B20–C7) GERGFFYTPKTRREAEDLQV 105818 DQ8   Yes  D– 
   44–63 (B20–C7) GERGFFYTPKTRREAEDLQV 105818 DQ6   Yes  D– 
   45–61 (B21–C5) ERGFFYTPKTRREAEDL 933281 Class II  Yes   D+ 
   46–61 (B22–C5) RGFFYTPKTRREAEDL 418483 DQ8   Yes Yes B– 
   48–60 (B24–C4) FFYTPKTRREAED 103168 DR0301  Yes   D+ 
   48–60 (B24–C4) FFYTPKTRREAED 103168 Class II  Yes   D+ 
   49–64 (B25–C8) FYTPKTRREAEDLQVG 102451 Class II  Yes   C– 
   49–65 (B25–C9) FYTPKTRREAEDLQVGQ 103191 Class II  Yes   D+ 
   52–68 (B28–C12) PKTRREAEDLQVGQVEL 933289 Class II  Yes   D+ 
   54–69 (B30–C13) TRREAEDLQVGQVELG 538096 DQ2/DQ8  Yes   C– 
   54–69 (B30–C13) TRREAEDLQVG(Q→E)VELG 910786 DQ2/DQ8  Yes   C– 
   54–69 (B30–C13) TRREAEDL(Q→E)VG(Q→E)VELG 910787 DQ2/DQ8  Yes   C– 
   54–70 (B30–C14) TRREAEDLQVGQVELGG 104316 Class II  Yes   D+ 
   55–70 (B31–C14) RREAEDLQVGQVELGG 840928 DQ8   Yes Yes B– 
   57–87 (C1–C31) EAEDLQVGQVELGGGPGAGSLQPLALEGSLQ 104452 Class II  Yes   D+ 
   57–70 (C1–C14) EAEDLQVGQVELGG 857864 DQ8  Yes   D+ 
   58–67 (C2–C11) AEDLQVGQVE 174367 DQ8  Yes   D+ 
   59–74 (C3–C18) EDLQVGQVELGGGPGA 102379 Class II  Yes   C– 
   59–75 (C3–C19) EDLQVGQVELGGGPGAG 103869 Class II  Yes   D+ 
   61–76 (C5–C20) LQVGQVELGGGPGAGS 840894 DQ8   Yes Yes B– 
   64–76 (C8–C20) GQVELGGGPGAGS 952145 DQ8  Yes   D+ 
   64–80 (C8–C24) GQVELGGGPGAGSLQPL 103948 Class II  Yes   D+ 
   64–83 (C8–C27) GQVELGGGPGAGSLQPLALE 105845 DQ6   Yes  D– 
   65–73 (C9–C17) QVELGGGPG 174710 DQ8 Yes    C+ 
   65–75 (C9–C19) QVELGGGPGAG 858014 DQ8 Yes    C+ 
   66–73 (C10–C17) VELGGGPG 858095 DQ8 Yes    C+ 
   66–74 (C10–C18) VELGGGPGA 174788 DQ8 Yes    C+ 
   66–82 (C10–C26) VELGGGPGAGSLQPLAL 933294 Class II  Yes   D+ 
   69–85 (C13–C29) GGGPGAGSLQPLALEGS 103922 Class II  Yes   D+ 
   69–88 (C13–C32) GGGPGAGSLQPLALEGSLQK 134060 DR0401   Yes Yes B– 
   69–88 (C13–C32) GGGPGAGSLQPLALEGSLQK 134060 Class II  Yes   D+ 
   69–88 (C13–C32) GGGPGAGSLQPLALEGSLQK 134060 DR4  Yes  Yes B+ 
   70–86 (C14–C30) GGPGAGSLQPLALEGSL 103215 DQ8   Yes Yes B– 
   72–83 (C16–C27) PGAGSLQPLALE 857990 DQ8  Yes   D+ 
   72–86 (C16–C30) PGAGSLQPLALEGSL 913900 DQ8/DQ8-trans  Yes   D+ 
   73–82 (C17–C26) GAGSLQPLAL 174496 DQ8-trans  Yes   D+ 
   73–89 (C17–C33) GAGSLQPLALEGSLQKR 604401 Class II  Yes   D+ 
   73–89 (C17–C33) GAGSLQPLALEGSLQKR 604401 DQ8-trans Yes    C+ 
   73–90 (C17–A1) GAGSLQPLALEGSLQKRG 102454 DR0401  Yes Yes Yes B+ 
   73–92 (C17–A3) GAGSLQPLALEGSLQKRGIV 138770 DR0401  Yes   D+ 
   74–82 (C18–C26) AGSLQPLAL 174376 DQ8 Yes    C+ 
   74–83 (C18–C27) AGSLQPLALE 174377 DQ8 Yes    C+ 
   74–90 (C18–A1) AGSLQPLALEGSLQKRG 103791 Class II  Yes   D+ 
   74–90 (C18–A1) AGSLQPLALEGSLQKRG 103791 DR0401  Yes   D+ 
   74–93 (C18–A4) AGSLQPLALEGSLQKRGIVE 105666 DQ8   Yes  D– 
   74–93 (C18–A4) AGSLQPLALEGSLQKRGIVE 105666 DQ6   Yes  D– 
   75–92 (C19–A3) GSLQPLALEGSLQKRGIV 104511 DR0401  Yes Yes Yes B+ 
   75–92 (C19–A3) GSLQPLALEGSLQKRGIV 104511 DR4  Yes  Yes B+ 
   76–85 (C20–C29) SLQPLALEGS 174743 DQ8-trans Yes Yes   C+ 
   76–86 (C20–C30) SLQPLALEGSL 858046 DQ8-trans Yes    C+ 
   76–86 (C20–C30) SLQPLALEGSL 858046 DR0401  Yes   D+ 
   76–87 (C20–C31) SLQPLALEGSLQ 858047 DQ2-trans  Yes   D+ 
   76–90 (C20–A1) SLQPLALEGSLQKRG 101243 DR0401 Yes Yes   C+ 
   78–94 (C22–A5) QPLALEGSLQKRGIVEQ 462422 DR0401   Yes Yes B– 
   78–94 (C22–A5) QPLALEGSLQKRGIVEQ 462422 DR4  Yes  Yes B+ 
   78–86 (C22–C30) QPLALEGSL 174706 DQ2  Yes   D+ 
   78–87 (C22–C31) QPLALEGSLQ 174707 DR0401  Yes   D+ 
   79–95 (C23–A6) PLALEGSLQKRGIVEQC 104177 Class II  Yes   D+ 
   80–86 (C24–C30) LALEGSL 857935 DQ2  Yes   D+ 
   80–86 (C24–C30) LALEGSL 857935 DQ2-trans  Yes   D+ 
   80–86 (C24–C30) LALEGSL 857935 DQ8  Yes   D+ 
   80–88 (C24–C32) LALEGSLQK 103335 DR0401  Yes   D+ 
   80–96 (C24–A7) LALEGSLQKRGIVEQCC 933284 Class II  Yes   D+ 
   80–97 (C24–A8) LALEGSLQKRGIVEQCCT 840879 DQ8   Yes Yes B– 
   84–100 (C28–A11) GSLQKRGIVEQCCTSIC 103953 Class II  Yes   D+ 
   85–101 (C29–A12) SLQKRGIVEQCCTSICS 104628 DR0401   Yes Yes B– 
   87–103 (C31–A14) QKRGIVEQCCTSICSLY 933290 Class II  Yes   D+ 
   88–102 (C32–A13) KRGIVEQCCTSICSL 103321 DR4  Yes   C– 
   90–101 (A1–A12) GIVEQCCTSICS 104808 DR  Yes   D+ 
   90–101 (A1–A12) GIVEQCCTSICS 104808 DQ  Yes   D+ 
   90–102 (A1–A13) GIVEQCCTSICSL (vicinal disulfide 95–96) 910744 DR  Yes   C– 
   90–104 (A1–A15) GIVEQCCTSICSLYQ 103926 DR0401 Yes    C+ 
   90–105 (A1–A16) GIVEQCCTSICSLYQL 923350 Class II  Yes   D+ 
   92–104 (A3–A15) VEQCCTSICSLYQ 102889 Class II  Yes   D+ 
   92–110 (A3–A21) VEQCCTSICSLYQLENYCN 840960 DQ8   Yes Yes B− 
   94–105 (A5–A16) QCCTSICSLYQL 104945 Class II  Yes   D+ 
   94–110 (A5–A21) QCCTSICSLYQLENYCN 106028 Class II  Yes   D+ 
   94–110 (A5–A21) QCCTSICSLYQLENYCN 106028 DQ8   Yes  D– 
   94–110 (A5–A21) QCCTSICSLYQLENYCN 106028 DQ6   Yes  D– 
   95–110 (A6–A21) CCTSICSLYQLENYCN 103824 Class II  Yes   D+ 
   98–110 (A9–A21) SICSLYQLENYCN 104979 Class II  Yes   D+ 
S100β (S100B6–25 KAMVALIDVFHQYSGREGDK 422018 DR0401  Yes  Yes B+ 
   21–36 REGDKHKLKKSELKEL 422069 DR0401  Yes  Yes B+ 
   25–46 KHKLKKSELKELINNELSHFLE 422020 DR0401  Yes  Yes B+ 
   68–92 ECDFQEFMAFVAMVTTACHEFFEHE 421964 DR0401  Yes  Yes B+ 
ZnT8 (SLC30A81–27 MEFLERTYLVNDKAAKM(Y→H)AFTLESVEL 174655 DR4  Yes   D+ 
   5–19 ERTYLVNDKAAKM(Y→H)A 186664 Class II  Yes   D+ 
   15–41 AKM(Y→H)AFTLESVELQQKPVNKDQCPRER 174379 DR4  Yes   D+ 
   64–90 ANEYAYAKWKLCSASAICFIFMIAEVV 174388 DR4  Yes   D+ 
   67–80 YAYAKWKLCSASAI 186722 Class II  Yes   D+ 
   78–104 SAICFIFMIAEVVGGHIAGSLAVVTDA 174730 DR4  Yes   D+ 
   106–132 HLLIDLTSFLLSLFSLWLSSKPPSKRL 174539 DR4  Yes   D+ 
   120–146 SLWLSSKPPSKRLTFGWHRAEILGALL 174745 DR3  Yes   D+ 
   120–146 SLWLSSKPPSKRLTFGWHRAEILGALL 174745 DR4  Yes   D+ 
   124–138 SSKPPSKRLTFGWHR 186707 Class II  Yes   D+ 
   134–174 FGWHRAEILGALLSILCIWVVTGVLVYLACERLLYPDYQIQ 174484 DR3  Yes   D+ 
   134–174 FGWHRAEILGALLSILCIWVVTGVLVYLACERLLYPDYQIQ 174484 DR4  Yes   D+ 
   162–188 ACERLLYPDYQIQATVMIIVSSCAVAA 174364 DR4  Yes   D+ 
   197–223 HQRCLGHNHKEVQANASVRAAFVHALG 174542 DR4  Yes   D+ 
   211–237 NASVRAAFVHALGDLFQSISVLISALI 174667 DR4  Yes   D+ 
   244–258 YKIADPICTFIFSIL 186725 Class II  Yes   D+ 
   253–279 FIFSILVLASTITILKDFSILLMEGVP 174486 DR4  Yes   D+ 
   254–268 IFSILVLASTITILK 186680 Class II  Yes   D+ 
   266–285 ILKDFSILLMEGVPKSLNYS 644825 DR  Yes   C– 
   267–293 LKDFSILLMEGVPKSLNYSGVKELILA 174637 DR4  Yes   D+ 
   271–283 SILLMEGVPKSLN 138810 DR0401  Yes   D+ 
   295–321 DGVLSVHSLHIWSLTMNQVILSAHVAT 174440 DR4  Yes   D+ 
   309–335 TMNQVILSAHVATAASRDSQVVRREIA 174759 DR4  Yes   D+ 
   323–356 ASRDSQVVRREIAKALSKSFTMHSLTIQMESPVD 174399 DR3  Yes   D+ 
   323–356 ASRDSQVVRREIAKALSKSFTMHSLTIQMESPVD 174399 DR4  Yes   D+ 
   326–340 DSQVVRREIAKALSK 186661 Class II  Yes   D+ 
   330–349 VRREIAKALSKSFTMHSLTI 651976 DR  Yes   C− 
   352–366 ESPVDQDPDCLFCED 186665 Class II  Yes   D+ 
Antigen (gene)PositionSequenceIEDB#aMHCHuman islets, pLNsbHuman blood, spleenbHLA-Tg mousebNPPcEvidencedReporting articlese
CHGA (CHGA) 342–355 WSKMDQLAKELTAE 226405 DQ8  Yes  Yes B+ 
DMK (DMPK) 9–28 RLQQLVLDPGFLGLEPLLDL 138808 DR0401  Yes   C– 
GAD65 (GAD21–20 MASPGSGFWSFGSEDGSGDS 101054 Class II  Yes   D+ 
   1–20 MASPGSGFWSFGSEDGSGDS 101054 DR0401  Yes   C– 
   47–66 LLYGDAEKPAESGGSQPPRA 105302 Class II  Yes   D+ 
   73–92 CACDQKPCSCSKVDVNYAFL 142554 DR  Yes   C– 
   73–92 CACDQKPCSCSKVDVNYAFL 142554 DR0401  Yes   C– 
   81–100 SCSKVDVNYAFLHATDLLPA 104234 DR  Yes   C– 
   86–103 DVNYAFLHATDLLPACDG 186992 DR4  Yes   D+ 
   88–99 NYAFLHATDLLP 104163 DR0101  Yes  Yes A– 
   88–99 NYAFLHATDLLP 104163 DRB5  Yes   C– 
   89–108 YAFLHATDLLPACDGE(R→Cit)PTL 230433 DR0401  Yes   C– 
   101–115 CDGERPTLAFLQDVM 6101 DQ  Yes   D+ 
   105–124 RPTLAFLQDVMNILLQYVVK 143044 DR0401  Yes   C– 
   108–129 LAFLQDVMNILLQYVVKSFDRS 105275 Class II  Yes   D+ 
   113–132 DVMNILLQYVVKSFDRSTKV 138762 DR0401  Yes  Yes A– 
   113–132 DVMNILLQYVVKSFDRSTKV 138762 DR  Yes   C– 
   113–132 DVMNILLQYVVKSFDRSTKV 138762 DRB4  Yes   D+ 
   115–127 MNILLQYVVKSFD 100311 DR0401 Yes  Yes Yes A+ 
   115–127 MNILLQYVVKSFD 100311 Class II  Yes   D+ 
   115–127 MNILL(Q→E)YVVKSFD 230399 DR0401  Yes   C– 
   115–130 MNILLQYVVKSFDRST 104903 DR0401   Yes Yes 
   116–129 NILLQYVVKSFDRS 102675 DRB4  Yes   C– 
   116–127 NILLQYVVKSFD 104150 DRB4  Yes   C– 
   121–140 YVVKSFDRSTKVIDFHYPNE 102974 DQ8  Yes Yes Yes A– 
   126–140 FDRSTKVIDFHYPNE 103164 DQ  Yes   D+ 
   146–165 NWELADQPQNLEEILMHCQT 103455 DR1601  Yes  Yes A– 
   153–172 P(Q→E)NLEEILMHC(Q→E)TTLKYAIK 230405 DR0401  Yes   C– 
   157–176 EEILMHCQTTLKYAIKTGHP 105161 Class II  Yes   D+ 
   172–191 KTGHPRYFNQLSTGLDMVGL 105271 Class II  Yes   D+ 
   173–187 TGHPRYFNQLSTGLD 104649 Class II  Yes   D+ 
   174–185 GHPRYFNQLSTG 103219 DR0401  Yes  Yes A– 
   175–190 HPRYFNQLSTGLDMVG 187007 DR4  Yes   D+ 
   177–196 RYFNQLSTGLDMVGLAADWL 143056 DR  Yes   C– 
   200–217 ANTNMFTYEIAPVFVLLE 103808 DR8 or DR9  Yes   C– 
   201–220 NTNMFTYEIAPVFVLLEYVT 102698 DQ8   Yes Yes B– 
   201–220 NTNMFTYEIAPVFVLLEYVT 102698 DR0401  Yes  Yes A– 
   202–221 TNMFTYEIAPVFVLLEYVTL 105004 Class II  Yes   D+ 
   203–226 NMFTYEIAPVFVLLEYVTLKKMRE 187017 DR4  Yes   D+ 
   206–220 TYEIAPVFVLLEYVT 67328 DQ  Yes   D+ 
   209–228 IAPVFVLLEYVTLKKMREII 142728 DRB4  Yes   D+ 
   217–236 EYVTLKKMREIIGWPGGSGD 104481 DR  Yes   C– 
   225–244 REIIGWPGGSGDGIFSPGGA 143023 DR  Yes   C– 
   231–250 PGGSGDGIFSPGGAISNMYA 102715 DQ8   Yes Yes B– 
   232–251 GGSGDGIFSPGGAISNMYAM 105216 Class II  Yes   D+ 
   243–267 GAISNMYAMMIARFKMFPEVKEKGM 186999 DR4  Yes   D+ 
   247–266 NMYAMMIARFKMFPEVKEKG 45043 DR3  Yes   C– 
   247–266 NMYAMMIARFKMFPEVKEKG 45043 Class II  Yes   C– 
   247–279 NMYAMMIARFKMFPEVKEKGMAALPRLIAFTSE 101931 Class II  Yes   D+ 
   248–257 MYAMMIARFK 104140 DRB5  Yes  Yes A– 
   248–259 MYAMMIARFKMF 104141 DR0101  Yes  Yes A– 
   249–268 YAMMIARFKMFPEVKEKGMA 143224 DR  Yes   C– 
   250–266 AMMIARFKMFPEVKEKG 234479 DQ8  Yes   C– 
   251–270 MMIARFKMFPEVKEKGMAAL 104118 DR12  Yes   C– 
   252–266 MIARFKMFPEVKEKG 104114 DR0404  Yes   C– 
   252–266 MIARFKMFPEVKEKG 104114 Class II  Yes   D+ 
   254–276 ARFKMFPEVKEKGMAALPRLIAF 118749 Class II  Yes   D+ 
   260–279 PEVKEKGMAALPRLIAFTSE 105471 Class II  Yes   D+ 
   261–275 EVKEKGMAALPRLIA 186666 Class II  Yes   D+ 
   261–280 EVKEKGMAALPRLIAFTSEH 103893 DQ8  Yes   C– 
   264–287 EKGMAALPRLIAFTSEHSHFSLKK 186995 DR4  Yes   D+ 
   265–284 KGMAALPRLIAFTSEHSHFS 142811 DR0401  Yes  Yes A– 
   265–284 KGMAALP(R→Cit)LIAFTSEHSHFS 230391 DR0401  Yes   C– 
   265–284 KGMAALPRLIAFTSEHSHFS 142811 DR  Yes   C– 
   266–285 GMAALPRLIAFTSEHSHFSL 104502 DR0401  Yes   D+ 
   270–283 LPRLIAFTSEHSHF 103379 DR0401  Yes  Yes A– 
   270–284 LPRLIAFTSEHSHFS 103380 DRB4  Yes  Yes A– 
   270–287 LPRLIAFTSEHSHFSLKK 157610 DR0401  Yes   D+ 
   271–285 PRLIAFTSEHSHFSL 104934 DR0401   Yes Yes 
   272–283 RLIAFTSEHSHF 103556 DRB4  Yes  Yes A– 
   273–292 LIAFTSEHSHFSLKKGAAAL 138782 DR0401  Yes  Yes A– 
   273–292 LIAFTSEHSHFSLKKGAAAL 138782 DR  Yes   C– 
   274–286 IAFTSEHSHFSLK 25275 DR0401 Yes Yes Yes Yes A+ 
   274–286 IAFTSEHSHFSLK 25275 Class II  Yes   D+ 
   276–284 FTSEHSHFS 231904 DR0404  Yes   C– 
   289–303 AAALGIGTDSVILIK 130713 Class II  Yes   D+ 
   290–309 AALGIGTDSVILIKCDERGK 104403 Class II  Yes   D+ 
   297–316 DSVILIKCDERGKMIPSDLE 142591 DR0401  Yes   C– 
   305–324 DERGKMIPSDLERRILEAKQ 105133 DR0401  Yes  Yes A– 
   320–339 LEAKQKGFVPFLVSATAGTT 105281 Class II  Yes   D+ 
   321–340 EAKQKGFVPFLVSATAGTTV 103867 DR0401  Yes  Yes A– 
   335–352 TAGTTVYGAFDPLLAVAD 226392 DR3  Yes   D+ 
   338–352 TTVYGAFDPLLAVAD 187030 DR4  Yes   D+ 
   353–372 ICKKYKIWMHVDAAWGGGLL 142730 Class II  Yes   C– 
   353–372 ICKKYKIWMHVDAAWGGGLL 142730 DRB4  Yes   D+ 
   354–372 CKKYKIWMHVDAAWGGGLL 186990 DR4  Yes   D+ 
   356–370 KYKIWMHVDAAWGGG 104868 DR0401   Yes Yes 
   368–388 GGGLLMSRKHKWKLSGVERAN 103921 DPw2  Yes   C– 
   369–388 GGLLMSRKHKWKLSGVERAN 142674 DR  Yes   C– 
   369–392 GGLLMSRKHKWKLSGVERANSVTW 187001 DR4  Yes   D+ 
   376–390 KHKWKLSGVERANSV 104852 DR0401   Yes Yes 
   377–396 HKWKLSGVERANSVTWNPHK 142717 DR0401  Yes   C– 
   377–396 HKWKLSGVERANSVTWNPHK 142717 DR  Yes   C– 
   385–404 ERANSVTWNPHKMMGVPLQC 105169 Class II  Yes   D+ 
   405–424 SALLVREEGLMQNCNQMHAS 187026 DR4  Yes   D+ 
   413–431 GLMQNCNQMHASYLFQQDK 103939 DR0101  Yes   C– 
   416–435 QNCNQMHASYLFQQDKHYDL 105488 Class II  Yes   D+ 
   431–445 KHYDLSYDTGDKALQ 103306 DQ  Yes   D+ 
   433–452 YDLSYDTGDKALQCGRHVDV 143226 DR0401  Yes  Yes A– 
   433–452 YDLSYDTGDKALQCGRHVDV 143226 Class II  Yes   C– 
   446–466 CGRHVDVFKLWLMWRAKGTTG 105120 Class II  Yes   D+ 
   450–470 VDVFKLWLMWRAKGTTGFEAH 187032 DR4  Yes   D+ 
   461–473 AKGTTGFEAHVDK 103035 DQ  Yes   D+ 
   462–483 KGTTGFEAHVDKCLELAEYLYN 105261 Class II  Yes   D+ 
   471–490 VDKCLELAEYLYNIIKNREG 102882 DQ8   Yes Yes B– 
   473–492 KCLELAEYLYNIIKNREGYE 142807 DR0401  Yes  Yes A– 
   479–498 EYLYNIIKNREGYEMVFDGK 105173 Class II  Yes   D+ 
   480–496 YLYNIIKNREGYEMVFD 187035 DR4  Yes   D+ 
   481–495 LYNIIKNREGYEMVF 104898 DR0401   Yes Yes 
   491–510 YEMVFDGKPQHTNVCFWYIP 104352 DR3  Yes   C– 
   491–510 YEMVFDGKPQHTNVCFWYIP 104352 DQ5  Yes   C– 
   493–507 MVFDGKPQHTNVCFW 104575 Class II  Yes   D+ 
   494–513 VFDGKPQHTNVCFWYIPPSL 119539 Class II  Yes   D+ 
   501–520 HTNVCFWYIPPSLRTLEDNE 103978 DR1  Yes   C– 
   501–520 HTNVCFWYIPPSLRTLEDNE 103978 DR4  Yes   C– 
   504–518 VCFWYIPPSLRTLED 187031 DR4  Yes   D+ 
   505–519 CFWYIPPSLRTLEDN 101509 Class II  Yes   C– 
   505–519 CFWYIPPSLRTLEDN 101509 DQ8  Yes   D+ 
   506–518 FWYIPPSLRTLED 103913 Class II  Yes   D+ 
   509–528 IPPSLRTLEDNEERMSRLSK 102537 Class II  Yes   D+ 
   511–525 PSLRTLEDNEERMSR 104602 DR0401   Yes Yes 
   511–525 PSLRTLEDNEERMSR 104602 DR4  Yes   D+ 
   511–530 PSLRTLEDNEERMSRLSKVA 104189 DR3  Yes   C– 
   521–535 ERMSRLSKVAPVIKA 101609 Class II  Yes   C– 
   521–535 ERMSRLSKVAPVIKA 101609 DQ8  Yes   D+ 
   524–543 SRLSKVAPVIKARMMEYGTT 102085 Class II  Yes   D+ 
   529–548 VAPVIKARMMEYGTTMVSYQ 143155 DRB4  Yes   D+ 
   533–547 IKARMMEYGTTMVSY 104522 Class II  Yes   D+ 
   536–550 RMMEYGTTMVSYQPL 103560 DQ  Yes   D+ 
   536–550 RMMEYGTTMVSYQPL 103560 DQ8   Yes  D– 
   539–558 EYGTTMVSYQPLGDKVNFFR 105172 Class II  Yes   D+ 
   545–564 VSYQPLGDKVNFFRMVISNP 143204 DR0401  Yes  Yes A– 
   545–585 VSYQPLGDKVNFFRMVISNPAATHQDIDFLIEEIERLGQDL 102216 Class II  Yes   D+ 
   546–560 SYQPLGDKVNFFRMV 104994 DR0401   Yes Yes 
   550–570 LGDKVNFFRMVISNPAATHQD 187013 DR4  Yes   D+ 
   551–565 GDKVNFFRMVISNPA 104792 DR0401   Yes Yes 
   552–572 DKVNFFRMVISNPAATHQDID 119442 DR0401  Yes   C– 
   553–570 KVNFFRMVISNPAATHQD 102589 DR4  Yes  Yes A– 
   553–572 KVNFFRMVISNPAATHQDID 138779 DR0401  Yes  Yes A– 
   553–572 KVNFFRMVISNPAATHQDID 138779 Class II  Yes   C– 
   553–572 KVNFFRMVISNPAATHQDID 138779 DRB4  Yes   D+ 
   553–572 KVNFF(R→Cit)MVISNPAATHQDID 230397 DR0401  Yes   C– 
   554–573 VNFFRMVISNPAATHQDIDF 119541 Class II  Yes   D+ 
   554–567 VNFFRMVISNPAAT 158453 DR0401  Yes   D+ 
   554–575 VNFFRMVISNPAATHQDIDFLI 226402 DR4  Yes   D+ 
   555–567 NFFRMVISNPAAT 101067 DR0401 Yes Yes   C+ 
   555–567 NFFRMVISNPAAT 101067 DR0404  Yes   C– 
   555–567 NFFRMVISNPAAT 101067 DR4  Yes   D+ 
   556–570 FFRMVISNPAATHQD 104775 DR0401   Yes Yes 
   556–575 FFRMVISNPAATHQDIDFLI 103167 DR0401  Yes  Yes A– 
   563–575 NPAATHQDIDFLI 102684 DRB4  Yes  Yes A– 
   565–580 AATHQDIDFLIEEIER 104721 DR0401   Yes Yes 
   566–585 ATHQDIDFLIEEIERLGQDL 103818 Class II  Yes   D+ 
   566–585 ATHQDIDFLIEEIERLGQDL 103818 DRB4  Yes   D+ 
GRP78 (HSPA5195–209 VMRIINEPTAAAIAY 546164 DR0401  Yes   D+ 
   195–209 VM(R→Cit)IINEPTAAAIAY 858100 DR0401  Yes   D+ 
   292–305 VEKAK(R→Cit)ALSSQHQA 590605 Class II Yes    C+ 
   498–512 EVTFEIDVNGILRVT 857879 DR0401  Yes   D+ 
   498–512 EVTFEIDVNGIL(R→Cit)VT 857878 DR0401  Yes   C– 
   500–514 TFEIDVNGIL(R→Cit)VTAE 858056 DR0401  Yes   D+ 
HSP60 (HSPD131–50 KFGADARALMLQGVDLLADA 79582 Class II  Yes   D+ 
   136–155 NPVEIRRGVMLAVDAVIAEL 102687 Class II  Yes   D+ 
   242–256 AYVLLSEKKISSIQS 114753 DR  Yes   D+ 
   255–275 QSIVPALEIANAHRKPLVIIA 102750 Class II  Yes   D+ 
   280–294 GEALSTLVLNRLKVG 114829 DR  Yes   D+ 
   286–305 LVLNRLKVGLQVVAVKAPGF 40453 Class II  Yes   D+ 
   394–408 LAKLSDGVAVLKVGG 104547 Class II  Yes   D+ 
   436–455 IVLGGGCALLRCIPALDSLT 79579 Class II  Yes   D+ 
   466–485 EIIKRTLKIPAMTIAKNAGV 79540 Class II  Yes   D+ 
   511–530 VNMVEKGIIDPTKVVRTALL 102911 Class II  Yes   D+ 
HSP70 (HSPA1B1–20 MAKAAA(I→V)GIDLGTTYSCVGV 102642 Class II  Yes   D+ 
   166–185 GLNVLRIINEPTAAAIAYGL 102794 Class II  Yes   D+ 
   211–230 TIDDGIFEVKATAGDTHLGG 102846 Class II  Yes   D+ 
   226–245 THLGGEDFDNRLVNHFVEEF 102842 Class II  Yes   D+ 
   271–290 KRTLSSSTQASLEIDSLFEG 102579 Class II  Yes   D+ 
   391–410 LLLLDVAPLSLGLETAGGVM 102619 Class II  Yes   D+ 
   421–440 PTKQTQIFTTYSDNQPGVLI 102728 Class II  Yes   D+ 
   497–516 KANKITITNDKGRLSKEEIE 102548 Class II  Yes   D+ 
   512–531 KEEIERMVQEAEKYKAEDEV 102553 Class II  Yes   D+ 
IA-2 (PTPRN142–159 LQDIPTGSAPAAQHRLPQ 536828 DQ8 or DQ8-trans  Yes  Yes B+ 
   197–209 PSLSYEPALLQPY 104603 Class II  Yes   D+ 
   198–216 SLSYEPALL(Q→E)PYLFH(Q→E)FGS 914422 DQ8 Yes Yes   C+ 
   264–284 LPGPSPAQLFQDSGLLYLAQE 534743 DR4  Yes  Yes B+ 
   293–311 VPRLPEQGSSSRAEDSPEG 538314 DQ  Yes  Yes B+ 
   318–333 GDRGEKPASPAVQPDA 535895 DQ  Yes  Yes B+ 
   319–342 DRGEKPASPAVQPDAALQRLAAVL 534686 DR3  Yes  Yes B+ 
   449–488 SPLGQSQPTVAGQPSARPAAEEYGYIVTDQKPLSLAAGVK 534789 DR3  Yes  Yes B+ 
   467–482 AAEEYGYIVTD(Q→E)KPLS 914337 DQ8  Yes   C– 
   490–502 LEILAEHVHMSSG 104552 Class II  Yes   D+ 
   502–514 GSFINISVVGPAL 104510 Class II  Yes   D+ 
   523–536 QNLSLADVT(Q→E)(Q→E)AGL 914404 DQ8  Yes   C– 
   545–562 TGL(Q→E)IL(Q→E)TGVG(Q→E)REEAAA 914426 Class II Yes    C+ 
   545–562 TGL(Q→E)IL(Q→E)TGVG(Q→E)REEAAA 914426 DQ8 Yes Yes   C+ 
   575–587 RSVLLTLVALAGV 104618 Class II  Yes   D+ 
   601–618 RQHARQQDKERLAALGPE 104966 DQ8   Yes  D– 
   608–620 DKERLAALGPEGA 910445 Class II  Yes   D+ 
   616–633 GPEGAHGDTTFEYQDLCR 104813 DQ8   Yes  D– 
   646–663 EGPPEPSRVSSVSSQFSD 104764 DQ8   Yes  D– 
   654–674 VSSVSSQFSDAAQASPSSHSS 933295 DR4  Yes  Yes B+ 
   657–674 VSSQFSDAAQASPSSHSS 104677 DR0401  Yes   D+ 
   661–678 FSDAAQASPSSHSSTPSW 104781 DQ8   Yes  D– 
   685–700 ANMDISTGHMILAYME 105676 DR4  Yes   D+ 
   709–731 LAKEWQALCAYQAEPNTCATAQG 104546 DR0401  Yes  Yes B+ 
   709–733 LAKEWQALCAYQAEPNTCATAQGEG 874656 DR0401  Yes   D+ 
   709–736 LAKEWQALCAYQAEPNTCATAQGEGNIK 134126 Class II  Yes   D+ 
   713–728 WQALCAYQAEPNTCAT 106189 DR4  Yes   D+ 
   717–729 CAYQAEPNTCATA 104437 Class II  Yes   D+ 
   721–738 AEPNTCATAQGEGNIKKN 104723 DQ8   Yes  D– 
   745–760 PYDHARIKLKVESSPS 106021 DR4  Yes   D+ 
   751–770 IKLKVESSPSRSDYINASPI 104523 DR0401  Yes   C– 
   752–775 KLKVESSPSRSDYINASPIIEHDP 134118 Class II  Yes   D+ 
   752–775 KLKVESSPSRSDYINASPIIEHDP 134118 DR4  Yes  Yes B+ 
   766–783 NASPIIEHDPRMPAYIAT 104909 DQ8   Yes  D– 
   778–790 PAYIATQGPLSHT 104590 Class II  Yes   D+ 
   787–802 LSHTIADFWQMVWESG 105943 DR4  Yes   D+ 
   793–808 DFWQMVWESGCTVIVM 105709 DR4  Yes   D+ 
   793–817 DFWQMVWESGCTVIVMLTPLVEDGV 233467 Class II  Yes   D+ 
   797–809 MVWESGCTVIVML 910496 Class II  Yes   D+ 
   797–817 MVWESGCTVIVMLTPLVEDGV 104578 DR0401  Yes   D+ 
   799–814 WESGCTVIVMLTPLVE 106184 DR3-DQ2  Yes   D+ 
   799–814 WESGCTVIVMLTPLVE 106184 DR4  Yes   D+ 
   803–815 CTVIVMLTPLVED 104441 Class II  Yes   D+ 
   804–816 TVIVMLTPLVEDG 910528 Class II  Yes   D+ 
   805–817 VIVMLTPLVEDGV 133730 Class II  Yes   C– 
   805–820 VIVMLTPLVEDGVKQC 106162 DR3-DQ2  Yes   D+ 
   805–820 VIVMLTPLVEDGVKQC 106162 DR4  Yes   D+ 
   826–843 DEGASLYHVYEVNLVSEH 922741 DQ8   Yes  D– 
   830–842 SLYHVYEVNLVSE 104629 Class II  Yes   D+ 
   831–850 LYHVYEVNLVSEHIWCEDFL 104566 DP0401  Yes   C– 
   841–856 SEHIWCEDFLVRSFYL 106100 DR3-DQ2  Yes   D+ 
   841–856 SEHIWCEDFLVRSFYL 106100 DR4  Yes   D+ 
   841–860 SEHIWCEDFLVRSFYLKNVQ 104620 DP0401  Yes   C– 
   841–860 SEHIWCEDFLVRSFYLKNVQ 104620 DR4  Yes   D+ 
   845–860 WCEDFLVRSFYLKNVQ 106182 DR4  Yes   D+ 
   847–862 EDFLVRSFYLKNVQTQ 105741 DR3-DQ2  Yes   D+ 
   847–862 EDFLVRSFYLKNVQTQ 105741 DR4  Yes   D+ 
   853–872 SFYLKNVQTQETRTLTQFHF 134229 DR4  Yes   D+ 
   854–866 FYLKNVQTQETRT 910467 Class II  Yes   D+ 
   854–872 FYLKNVQTQETRTLTQFHF 104493 DR0401  Yes   D+ 
   889–904 DFRRKVNKCYRGRSCP 105708 DR4-DQ8  Yes   D+ 
   918–930 TYILIDMVLNRMA 104662 Class II  Yes   D+ 
   919–934 YILIDMVLNRMAKGVK 106198 DR3-DQ2  Yes   D+ 
   919–934 YILIDMVLNRMAKGVK 106198 DR4  Yes   D+ 
   931–948 KGVKEIDIAATLEHVRDQ 922742 DQ8   Yes  D– 
   933–945 VKEIDIAATLEHV 910531 Class II  Yes   D+ 
   955–975 SKDQFEFALTAVAEEVNAILK 104626 DR0401  Yes   D+ 
   957–969 DQFEFALTAVAEE 104447 Class II  Yes   D+ 
   959–974 FEFALTAVAEEVNAIL 105774 DR4  Yes   D+ 
   961–979 FALTAVAEEVNAILKALPQ 104772 DQ8   Yes  D– 
IAPP (IAPP65–84 VGSNTYGK(R→Cit)NAVEVLK(R→Cit)EPL 590688 Class II Yes    C+ 
   65–84 VGSNTYGK(R→Cit)NAVEVLK(R→Cit)EPL 590688 DQ8  Yes   C– 
ICA69 (ICA136–47 AFIKATGKKEDE 104413 Class II  Yes   D+ 
IGRP (G6PC213–25 QHLQKDYRAYYTF 106039 DR0301  Yes   C– 
   17–36 KDYRAYYTFLNFMSNVGDPR 138777 DR0401  Yes   D+ 
   23–35 YTFLNFMSNVGDP 106206 DR0401  Yes   C– 
   177–196 HQVILGVIGGMLVAEAFEHT 644404 Class II  Yes   C– 
   226–238 RVLNIDLLWSVPI 106096 DR0301  Yes   C– 
   241–260 KWCANPDWIHIDTTPFAGLV 138780 DR0401  Yes   D+ 
   241–260 KWCANPDWIHIDTTPFAGLV 138780 Class II  Yes   C– 
   247–259 DWIHIDTTPFAGL 105736 DR0401  Yes   C– 
   305–324 QLYHFLQIPTHEEHLFYVLS 648592 DR  Yes   C– 
INS (INS1–15 (L1–L15) MALWMRLLPLLALLA 840899 DQ8   Yes Yes B– 
   1–16 (L1–L16) MALWMRLLPLLALLAL 103406 Class II  Yes   D+ 
   1–24 (L1–L24) MALWMRLLPLLALLALWGPDPAAA 105962 DQ8   Yes  D– 
   1–24 (L1–L24) MALWMRLLPLLALLALWGPDPAAA 105962 DQ6   Yes  D– 
   5–20 (L5–L20) MRLLPLLALLALWGPD 923548 Class II  Yes   D+ 
   8–23 (L8–L23) LPLLALLALWGPDPAA 840893 DQ8   Yes Yes B– 
   9–24 (L9–L24) PLLALLALWGPDPAAA 923645 Class II  Yes   D+ 
   9–28 (L9–B4) PLLALLALWGPDPAAAFVNQ 142953 DRB4  Yes   D+ 
   11–26 (L11–B2) LALLALWGPDPAAAFV 104548 DR0401   Yes Yes B– 
   13–28 (L13–B4) LLALWGPDPAAAFVNQ 923488 Class II  Yes   D+ 
   14–33 (L14–B9) LALWGPDPAAAFVNQHLCGS 105917 DQ8   Yes  D– 
   14–33 (L14–B9) LALWGPDPAAAFVNQHLCGS 105917 DQ6   Yes  D– 
   16–30 (L16–B6) LWGPDPAAAFVNQHL 933452 DQ8   Yes Yes B– 
   17–24 (L17–24) WGPDPAAA 103728 DQ8-trans  Yes  Yes B+ 
   17–32 (L17–B8) WGPDPAAAFVNQHLCG 923967 Class II  Yes   D+ 
   18–30 (L18–B6) GPDPAAAFVNQHL 933381 DQ8   Yes Yes B– 
   20–35 (L20–B11) DPAAAFVNQHLCGSHL 840818 DQ8   Yes Yes B– 
   21–36 (L21–B12) PAAAFVNQHLCGSHLV 104589 DR0401   Yes Yes B– 
   21–36 (L21–B12) PAAAFVNQHLCGSHLV 104589 Class II  Yes   D+ 
   25–40 (B1–B16) FVNQHLCGSHLVEALY 840840 Class II  Yes   D+ 
   25–40 (B1–B16) FVNQHLCGSHLVEALY 840840 DQ8   Yes Yes B– 
   25–41 (B1–B17) FVNQHLCGSHLVEALYL 103908 Class II  Yes   D+ 
   30–46 (B6–B22) LCGSHLVEALYLVCGER 104030 Class II  Yes   D+ 
   30–46 (B6–B22) LCGSHLVEALYLVCGER 104030 DQ8  Yes   C– 
   31–47 (B7–B23) CGSHLVEALYLVCGERG 933280 Class II  Yes   D+ 
   33–47 (B9–B23) SHLVEALYLVCGERG 58388 DQ8-trans Yes    C+ 
   33–47 (B9–B23) SHLVEALYLVCGERG 58388 DQ8 Yes Yes Yes Yes A+ 
   34–49 (B10–B25) HLVEALYLVCGERGFF 102517 Class II  Yes   C– 
   34–53 (B10–B29) HLVEALYLVCGERGFFYTPK 105241 DQ8   Yes  D– 
   34–53 (B10–B29) HLVEALYLVCGERGFFYTPK 105241 DQ6   Yes  D– 
   35–47 (B11–B23) LVEALYLVCGERG 104895 DQ8  Yes   C– 
   35–49 (B11–B25) LVEALYLVCGERGFF 104062 DQ8 Yes    C+ 
   35–51 (B11–B27) LVEALYLVCGERGFFYT 103394 DR1601  Yes   C– 
   35–51 (B11–B27) LVEALYLVCGERGFFYT 103394 Class II  Yes   D+ 
   37–47 (B13–B23) EALYLVCGERG 104759 DQ8  Yes   D+ 
   38–54 (B14–B30) ALYLVCGERGFFYTPKT 933279 Class II  Yes   D+ 
   40–55 (B16–B31) YLVCGERGFFYTPKTR 840972 DQ8   Yes Yes B– 
   40–56 (B16–B32) YLVCGERGFFYTPKTRR 923983 Class II  Yes   D+ 
   42–71 (B18–C15) VCGERGFFYTPKTRREAEDLQVGQVELGGG 105563 Class II  Yes   D+ 
   44–60 (B20–C4) GERGFFYTPKTRREAED 103917 Class II  Yes   D+ 
   44–63 (B20–C7) GERGFFYTPKTRREAEDLQV 105818 DQ8   Yes  D– 
   44–63 (B20–C7) GERGFFYTPKTRREAEDLQV 105818 DQ6   Yes  D– 
   45–61 (B21–C5) ERGFFYTPKTRREAEDL 933281 Class II  Yes   D+ 
   46–61 (B22–C5) RGFFYTPKTRREAEDL 418483 DQ8   Yes Yes B– 
   48–60 (B24–C4) FFYTPKTRREAED 103168 DR0301  Yes   D+ 
   48–60 (B24–C4) FFYTPKTRREAED 103168 Class II  Yes   D+ 
   49–64 (B25–C8) FYTPKTRREAEDLQVG 102451 Class II  Yes   C– 
   49–65 (B25–C9) FYTPKTRREAEDLQVGQ 103191 Class II  Yes   D+ 
   52–68 (B28–C12) PKTRREAEDLQVGQVEL 933289 Class II  Yes   D+ 
   54–69 (B30–C13) TRREAEDLQVGQVELG 538096 DQ2/DQ8  Yes   C– 
   54–69 (B30–C13) TRREAEDLQVG(Q→E)VELG 910786 DQ2/DQ8  Yes   C– 
   54–69 (B30–C13) TRREAEDL(Q→E)VG(Q→E)VELG 910787 DQ2/DQ8  Yes   C– 
   54–70 (B30–C14) TRREAEDLQVGQVELGG 104316 Class II  Yes   D+ 
   55–70 (B31–C14) RREAEDLQVGQVELGG 840928 DQ8   Yes Yes B– 
   57–87 (C1–C31) EAEDLQVGQVELGGGPGAGSLQPLALEGSLQ 104452 Class II  Yes   D+ 
   57–70 (C1–C14) EAEDLQVGQVELGG 857864 DQ8  Yes   D+ 
   58–67 (C2–C11) AEDLQVGQVE 174367 DQ8  Yes   D+ 
   59–74 (C3–C18) EDLQVGQVELGGGPGA 102379 Class II  Yes   C– 
   59–75 (C3–C19) EDLQVGQVELGGGPGAG 103869 Class II  Yes   D+ 
   61–76 (C5–C20) LQVGQVELGGGPGAGS 840894 DQ8   Yes Yes B– 
   64–76 (C8–C20) GQVELGGGPGAGS 952145 DQ8  Yes   D+ 
   64–80 (C8–C24) GQVELGGGPGAGSLQPL 103948 Class II  Yes   D+ 
   64–83 (C8–C27) GQVELGGGPGAGSLQPLALE 105845 DQ6   Yes  D– 
   65–73 (C9–C17) QVELGGGPG 174710 DQ8 Yes    C+ 
   65–75 (C9–C19) QVELGGGPGAG 858014 DQ8 Yes    C+ 
   66–73 (C10–C17) VELGGGPG 858095 DQ8 Yes    C+ 
   66–74 (C10–C18) VELGGGPGA 174788 DQ8 Yes    C+ 
   66–82 (C10–C26) VELGGGPGAGSLQPLAL 933294 Class II  Yes   D+ 
   69–85 (C13–C29) GGGPGAGSLQPLALEGS 103922 Class II  Yes   D+ 
   69–88 (C13–C32) GGGPGAGSLQPLALEGSLQK 134060 DR0401   Yes Yes B– 
   69–88 (C13–C32) GGGPGAGSLQPLALEGSLQK 134060 Class II  Yes   D+ 
   69–88 (C13–C32) GGGPGAGSLQPLALEGSLQK 134060 DR4  Yes  Yes B+ 
   70–86 (C14–C30) GGPGAGSLQPLALEGSL 103215 DQ8   Yes Yes B– 
   72–83 (C16–C27) PGAGSLQPLALE 857990 DQ8  Yes   D+ 
   72–86 (C16–C30) PGAGSLQPLALEGSL 913900 DQ8/DQ8-trans  Yes   D+ 
   73–82 (C17–C26) GAGSLQPLAL 174496 DQ8-trans  Yes   D+ 
   73–89 (C17–C33) GAGSLQPLALEGSLQKR 604401 Class II  Yes   D+ 
   73–89 (C17–C33) GAGSLQPLALEGSLQKR 604401 DQ8-trans Yes    C+ 
   73–90 (C17–A1) GAGSLQPLALEGSLQKRG 102454 DR0401  Yes Yes Yes B+ 
   73–92 (C17–A3) GAGSLQPLALEGSLQKRGIV 138770 DR0401  Yes   D+ 
   74–82 (C18–C26) AGSLQPLAL 174376 DQ8 Yes    C+ 
   74–83 (C18–C27) AGSLQPLALE 174377 DQ8 Yes    C+ 
   74–90 (C18–A1) AGSLQPLALEGSLQKRG 103791 Class II  Yes   D+ 
   74–90 (C18–A1) AGSLQPLALEGSLQKRG 103791 DR0401  Yes   D+ 
   74–93 (C18–A4) AGSLQPLALEGSLQKRGIVE 105666 DQ8   Yes  D– 
   74–93 (C18–A4) AGSLQPLALEGSLQKRGIVE 105666 DQ6   Yes  D– 
   75–92 (C19–A3) GSLQPLALEGSLQKRGIV 104511 DR0401  Yes Yes Yes B+ 
   75–92 (C19–A3) GSLQPLALEGSLQKRGIV 104511 DR4  Yes  Yes B+ 
   76–85 (C20–C29) SLQPLALEGS 174743 DQ8-trans Yes Yes   C+ 
   76–86 (C20–C30) SLQPLALEGSL 858046 DQ8-trans Yes    C+ 
   76–86 (C20–C30) SLQPLALEGSL 858046 DR0401  Yes   D+ 
   76–87 (C20–C31) SLQPLALEGSLQ 858047 DQ2-trans  Yes   D+ 
   76–90 (C20–A1) SLQPLALEGSLQKRG 101243 DR0401 Yes Yes   C+ 
   78–94 (C22–A5) QPLALEGSLQKRGIVEQ 462422 DR0401   Yes Yes B– 
   78–94 (C22–A5) QPLALEGSLQKRGIVEQ 462422 DR4  Yes  Yes B+ 
   78–86 (C22–C30) QPLALEGSL 174706 DQ2  Yes   D+ 
   78–87 (C22–C31) QPLALEGSLQ 174707 DR0401  Yes   D+ 
   79–95 (C23–A6) PLALEGSLQKRGIVEQC 104177 Class II  Yes   D+ 
   80–86 (C24–C30) LALEGSL 857935 DQ2  Yes   D+ 
   80–86 (C24–C30) LALEGSL 857935 DQ2-trans  Yes   D+ 
   80–86 (C24–C30) LALEGSL 857935 DQ8  Yes   D+ 
   80–88 (C24–C32) LALEGSLQK 103335 DR0401  Yes   D+ 
   80–96 (C24–A7) LALEGSLQKRGIVEQCC 933284 Class II  Yes   D+ 
   80–97 (C24–A8) LALEGSLQKRGIVEQCCT 840879 DQ8   Yes Yes B– 
   84–100 (C28–A11) GSLQKRGIVEQCCTSIC 103953 Class II  Yes   D+ 
   85–101 (C29–A12) SLQKRGIVEQCCTSICS 104628 DR0401   Yes Yes B– 
   87–103 (C31–A14) QKRGIVEQCCTSICSLY 933290 Class II  Yes   D+ 
   88–102 (C32–A13) KRGIVEQCCTSICSL 103321 DR4  Yes   C– 
   90–101 (A1–A12) GIVEQCCTSICS 104808 DR  Yes   D+ 
   90–101 (A1–A12) GIVEQCCTSICS 104808 DQ  Yes   D+ 
   90–102 (A1–A13) GIVEQCCTSICSL (vicinal disulfide 95–96) 910744 DR  Yes   C– 
   90–104 (A1–A15) GIVEQCCTSICSLYQ 103926 DR0401 Yes    C+ 
   90–105 (A1–A16) GIVEQCCTSICSLYQL 923350 Class II  Yes   D+ 
   92–104 (A3–A15) VEQCCTSICSLYQ 102889 Class II  Yes   D+ 
   92–110 (A3–A21) VEQCCTSICSLYQLENYCN 840960 DQ8   Yes Yes B− 
   94–105 (A5–A16) QCCTSICSLYQL 104945 Class II  Yes   D+ 
   94–110 (A5–A21) QCCTSICSLYQLENYCN 106028 Class II  Yes   D+ 
   94–110 (A5–A21) QCCTSICSLYQLENYCN 106028 DQ8   Yes  D– 
   94–110 (A5–A21) QCCTSICSLYQLENYCN 106028 DQ6   Yes  D– 
   95–110 (A6–A21) CCTSICSLYQLENYCN 103824 Class II  Yes   D+ 
   98–110 (A9–A21) SICSLYQLENYCN 104979 Class II  Yes   D+ 
S100β (S100B6–25 KAMVALIDVFHQYSGREGDK 422018 DR0401  Yes  Yes B+ 
   21–36 REGDKHKLKKSELKEL 422069 DR0401  Yes  Yes B+ 
   25–46 KHKLKKSELKELINNELSHFLE 422020 DR0401  Yes  Yes B+ 
   68–92 ECDFQEFMAFVAMVTTACHEFFEHE 421964 DR0401  Yes  Yes B+ 
ZnT8 (SLC30A81–27 MEFLERTYLVNDKAAKM(Y→H)AFTLESVEL 174655 DR4  Yes   D+ 
   5–19 ERTYLVNDKAAKM(Y→H)A 186664 Class II  Yes   D+ 
   15–41 AKM(Y→H)AFTLESVELQQKPVNKDQCPRER 174379 DR4  Yes   D+ 
   64–90 ANEYAYAKWKLCSASAICFIFMIAEVV 174388 DR4  Yes   D+ 
   67–80 YAYAKWKLCSASAI 186722 Class II  Yes   D+ 
   78–104 SAICFIFMIAEVVGGHIAGSLAVVTDA 174730 DR4  Yes   D+ 
   106–132 HLLIDLTSFLLSLFSLWLSSKPPSKRL 174539 DR4  Yes   D+ 
   120–146 SLWLSSKPPSKRLTFGWHRAEILGALL 174745 DR3  Yes   D+ 
   120–146 SLWLSSKPPSKRLTFGWHRAEILGALL 174745 DR4  Yes   D+ 
   124–138 SSKPPSKRLTFGWHR 186707 Class II  Yes   D+ 
   134–174 FGWHRAEILGALLSILCIWVVTGVLVYLACERLLYPDYQIQ 174484 DR3  Yes   D+ 
   134–174 FGWHRAEILGALLSILCIWVVTGVLVYLACERLLYPDYQIQ 174484 DR4  Yes   D+ 
   162–188 ACERLLYPDYQIQATVMIIVSSCAVAA 174364 DR4  Yes   D+ 
   197–223 HQRCLGHNHKEVQANASVRAAFVHALG 174542 DR4  Yes   D+ 
   211–237 NASVRAAFVHALGDLFQSISVLISALI 174667 DR4  Yes   D+ 
   244–258 YKIADPICTFIFSIL 186725 Class II  Yes   D+ 
   253–279 FIFSILVLASTITILKDFSILLMEGVP 174486 DR4  Yes   D+ 
   254–268 IFSILVLASTITILK 186680 Class II  Yes   D+ 
   266–285 ILKDFSILLMEGVPKSLNYS 644825 DR  Yes   C– 
   267–293 LKDFSILLMEGVPKSLNYSGVKELILA 174637 DR4  Yes   D+ 
   271–283 SILLMEGVPKSLN 138810 DR0401  Yes   D+ 
   295–321 DGVLSVHSLHIWSLTMNQVILSAHVAT 174440 DR4  Yes   D+ 
   309–335 TMNQVILSAHVATAASRDSQVVRREIA 174759 DR4  Yes   D+ 
   323–356 ASRDSQVVRREIAKALSKSFTMHSLTIQMESPVD 174399 DR3  Yes   D+ 
   323–356 ASRDSQVVRREIAKALSKSFTMHSLTIQMESPVD 174399 DR4  Yes   D+ 
   326–340 DSQVVRREIAKALSK 186661 Class II  Yes   D+ 
   330–349 VRREIAKALSKSFTMHSLTI 651976 DR  Yes   C− 
   352–366 ESPVDQDPDCLFCED 186665 Class II  Yes   D+ 
Nonconventional epitopes (excluding posttranslational modifications, which are included above)
Epitope typeEpitope sourcefSequenceIEDB#aMHCHuman islets, pLNsbHuman blood, spleenbHLA-Tg mousebNPPcEvidencedReporting articlese
INS hybrid C-pep:INS A GQVELGGGGIVEQCC 583306 Class II Yes    C+ 
INS hybrid C-pep:IAPP2 GQVELGGGNAVEVLK 505706 DQ8 (DR4?) Yes    C+ 
INS hybrid C-pep:NP-Y GQVELGGGSSPETLI 505707 DQ8 Yes    C+ 
INS hybrid C-pep:IAPP1 GQVELGGGTPIESHQ 583307 (DR4?) Yes    C+ 
Nonconventional epitopes (excluding posttranslational modifications, which are included above)
Epitope typeEpitope sourcefSequenceIEDB#aMHCHuman islets, pLNsbHuman blood, spleenbHLA-Tg mousebNPPcEvidencedReporting articlese
INS hybrid C-pep:INS A GQVELGGGGIVEQCC 583306 Class II Yes    C+ 
INS hybrid C-pep:IAPP2 GQVELGGGNAVEVLK 505706 DQ8 (DR4?) Yes    C+ 
INS hybrid C-pep:NP-Y GQVELGGGSSPETLI 505707 DQ8 Yes    C+ 
INS hybrid C-pep:IAPP1 GQVELGGGTPIESHQ 583307 (DR4?) Yes    C+ 
a

IEDB identifier (www.iedb.org).

b

Yes, T-cell responses observed using the indicated T-cell sources. See Supplementary Table 2 for details.

c

NPP, natural processing/presentation; yes, evidence is available. See Supplementary Table 2 for details.

d

See Fig. 2 for epitope scoring criteria.

e

See Supplementary Table 2 for details.

f

Underlining here and in the sequence column indicates the hybrid peptide extension. IAPP1 and IAPP2 are nonoverlapping regions of IAPP. NP-Y, neuropeptide Y.

HLA Nomenclature

The epitope discovery data covered by this review span many decades of work, diverse HLA-typing methods, and evolving standards for determining and reporting HLA restriction. Consequently, it was not possible for us to use a standardized set of HLA designations. For HLA class I, we consider typing with four-digit resolution to be definitive (e.g., HLA-A*02:01, HLA-B*07:02), with pairing of these chains with β2 microglobulin assumed. Two-digit nomenclature (e.g., HLA-A2, HLA-B15) is used as reported in original data (or to assess HLA coverage in Fig. 3, so that all of the compiled data could be included) and should be inferred to reflect a response with an unknown high-resolution subtyping.

For HLA class II, some assays did not attempt to define an HLA restriction, so these are designated as being “class II” restricted. Other studies used blocking antibodies to partially define an HLA restriction, so these are designated as being DR or DQ restricted (with no specific type or subtype implied). For HLA-DR, we consider typing of the β-chain with four-digit resolution to be definitive (e.g., HLA-DRB1*03:01, HLA-DRB1*04:04), with pairing of these chains to either of the dimorphic α-chains assumed. For convenience, DRB1 proteins are abbreviated DR0301, DR0401, etc. Two-digit nomenclature is always used for the rarely subtyped secondary DR proteins (e.g., HLA-DRB4, HLA-DRB5), for DRB1 restrictions as reported in original data, or to assess HLA coverage (so that all of the compiled data could be included). These designations should be inferred to reflect a response with an unknown high-resolution subtyping. For HLA-DP, definitive restriction would require both an α- and β-chain designated with four-digit resolution, but this was not done in the literature so we adopted a two-digit nomenclature (e.g., DP2), reflecting a response with an unknown α and no known high-resolution subtyping. For HLA-DQ, definitive restriction also requires both an α- and a β-chain designated with four-digit resolution. However, specific α-chain designations are often omitted in the literature. If available, we provide four-digit β-chain resolution (e.g., DQB1*02:01, DQB1*03:02). Pairing of these chains to the disease-associated α-chains (DQA1*05:01 and DQA1*03:01, respectively) is likely but cannot be assumed. When reported as such, we have retained historic serotype designations (e.g., DQ2 or DQ8, respectively, for the above examples) because further assignment was not available. For the few publications specifically addressing the formation of cross-haplotype trans-dimer pairings (e.g., DQ8-trans) as restriction elements, those designations are provided.

Epitope Grading

In development of an epitope scoring, or grading, system, our primary consideration was to devise a set of criteria that would succinctly reflect the current level of confidence that a given epitope is related to type 1 diabetes. While the grading system conveys our perspective on several useful and important criteria for epitope evaluation, we acknowledge the possibility of differing points of view. The key factors that were included in our scoring criteria (Fig. 2) were evidence of natural processing and presentation, the source of T cells used to define the epitope, and the isolation of T cells with confirmed recognition of the corresponding epitope. Natural processing and presentation were considered to be a critical factor for epitope relevance, primarily because, without such evidence, a putative T-cell epitope could be a mimotope peptide rather than a legitimate one. Consequently, evidence of natural processing and presentation was required for an epitope to be included in the upper grading strata (scores of B− or higher). Elution of the peptide from the corresponding HLA class I or class II molecule and identification by mass spectrometry are among the most stringent forms that this evidence could take, with arguably the ideal entry reporting such information for human β-cells and/or islet-associated antigen-presenting cells. However, we permitted processing and presentation evidence to take other less stringent forms as well, including T-cell responses to the protein source of the antigen or antigen-expressing cells and T-cell responses to DNA immunization in HLA-Tg mice. We acknowledge that some of these results are likely to be more reflective of in vivo processing and presentation than others, but weighting them differently would have resulted in an unwieldy grading system. However, to allow investigators to more heavily consider the evidence most relevant for their purposes, in the appropriate column of Supplementary Tables 1 and 2 we include the evidence for natural processing and presentation that supports each epitope.

Figure 2

T-cell epitope grading rubric. Our epitope scoring criteria include the source of T cells used to define the epitope (human islets/pLNs, human blood/spleen, or HLA-Tg mice), evidence of natural processing/presentation, and the isolation of T cells with confirmed recognition of the corresponding epitope. The figure depicts the minimal criteria that must be met for an epitope to be assigned the corresponding evidence grade, ranging from A+ to D−. Evidence of natural processing/presentation of an epitope may include peptide elution from MHC and identification by mass spectrometry, response to antigen protein or antigen-expressing cells, protein/DNA immunization response in HLA-Tg mice, or in vitro proteasome digestion yielding the correct C-terminus. The T-cell isolation criterion can be fulfilled with the availability of an epitope-reactive T-cell clone, line, or hybridoma or T-cell receptor–transduced T-cell line (of human or mouse origin).

Figure 2

T-cell epitope grading rubric. Our epitope scoring criteria include the source of T cells used to define the epitope (human islets/pLNs, human blood/spleen, or HLA-Tg mice), evidence of natural processing/presentation, and the isolation of T cells with confirmed recognition of the corresponding epitope. The figure depicts the minimal criteria that must be met for an epitope to be assigned the corresponding evidence grade, ranging from A+ to D−. Evidence of natural processing/presentation of an epitope may include peptide elution from MHC and identification by mass spectrometry, response to antigen protein or antigen-expressing cells, protein/DNA immunization response in HLA-Tg mice, or in vitro proteasome digestion yielding the correct C-terminus. The T-cell isolation criterion can be fulfilled with the availability of an epitope-reactive T-cell clone, line, or hybridoma or T-cell receptor–transduced T-cell line (of human or mouse origin).

Within the upper (A+ to B−) and lower (C+ to D−) grading strata, the source of T cells used to identify the epitope source was employed to further subdivide epitopes. Common sources of T cells included spleens from HLA-Tg mice, as well as human peripheral blood or, occasionally, spleens. Only a minor proportion of epitopes were identified or validated using human pLN-derived or islet-infiltrating T cells. Confidence was deemed highest for epitopes defined or confirmed using human pLN- or islet-derived T cells, followed by those defined using human peripheral blood or spleen-derived T cells, followed by those defined using HLA-Tg mice. Successful isolation of a T-cell clone, polyclonal line, hybridoma, or T-cell receptor–transduced T-cell line was considered to provide additional confidence; thus, epitopes with such evidence were scored an additional half grade higher than those without. In doing so, we reasoned that a T-cell epitope discovered using peptide/MHC multimers (Mmr) or enzyme-linked immunospot (ELISpot) could be more confidently validated as such with further confirmation by isolation of an epitope-reactive T-cell line or clone, particularly if only very low numbers of reactive cells were observed.

Initial confidence scores were assigned to each epitope on an individual basis for each reference. For epitopes supported by multiple references, these individual scores were then combined into a final overall score that reflected the cumulative level of confidence afforded by available publications as a whole. In some cases, that aggregated score could be considerably higher than any individual score. For example, GAD65 115–127 was reported as a DRB1*04:01 (DR0401)-restricted epitope in multiple studies (with individual scores ranging from B to C+). However, those studies cumulatively documented natural processing and presentation of the epitope, its recognition by human islet-resident T cells, and the isolation of a peptide-reactive hybridoma derived from HLA-Tg mice, resulting in a cumulative score of A+. All the information used to assign a grade is included in Supplementary Tables 1 and 2 and summarized in Tables 1 and 2. The number of publications associated with each epitope was not incorporated into our grading strategy, as doing so would have unfairly disadvantaged those epitopes that were more recently discovered. Nonetheless, we recognize that some may find this metric useful; thus, the number of reporting articles for each epitope is included in Tables 1 and 2, and the PMID number for each article can be found in Supplementary Tables 1 and 2.

CD8+ T-Cell Antigens and Epitopes

Although the strongest genetic determinant for susceptibility to type 1 diabetes is the expression of predisposing class II MHC molecules (10), multiple studies have revealed that certain class I MHC alleles, e.g., HLA-A*24:02, -B*39:01, and -B*39:06, also contribute to susceptibility (11). These findings suggest that class I MHC–restricted CD8+ T cells are important contributors to β-cell elimination. Consistent with this notion, β-cell–specific CD8+ T cells are present in the peripheral blood and islets of patients with type 1 diabetes, with the seminal report of β-cell–specific islet-infiltrating CD8+ T cells appearing <10 years ago (12). Furthermore, CD8+ T cells specific for peptides derived from the important β-cell antigen preproinsulin (INS) are cytotoxic to human islets (13,14). Preclinical models also provide strong support for the importance of autoreactive CD8+ T cells in β-cell demise; e.g., in NOD mice lacking class I MHC expression only on their β-cells, which would prevent their interaction with cytotoxic CD8+ T cells, insulitis develops, but the animals are largely protected from hyperglycemia (15). Thus, autoreactive CD8+ T cells are now recognized as promising targets for immune intervention strategies, and knowledge of their specificities is of considerable interest and importance.

From our cataloguing of the CD8+ T-cell epitopes in type 1 diabetes (Table 1), it can be seen that 16 conventional antigens have been identified to date. Figure 3C reveals that five of these account for the majority of known epitopes: INS, 42 epitopes; zinc transporter 8 (ZnT8), 33; GAD65, 18; insulinoma-associated protein 2 (IA-2), 9; and IGRP, 8. Of these five antigens, IGRP is unique in having first been discovered as relevant to type 1 diabetes from studies in the NOD mouse model of the disease (16), which exemplifies the utility of animal models. Moreover, IGRP is also unique because, contrary to the other major antigens INS, ZnT8, GAD65, and IA-2, anti-IGRP autoantibodies have not been described to date. For the remaining 11 antigens, three or fewer epitopes have been defined in each. However, the majority of these antigens have only recently been discovered.

Figure 3

HLA restriction and grade and antigen distributions for CD8+ and CD4+ T-cell epitopes of β-cell antigens. AC: HLA class I–restricted epitopes. DF: HLA class II–restricted epitopes. A and D: The HLA restrictions for the 142 CD8+ T-cell epitopes in Table 1 and the 143 CD4+ T-cell epitopes in Supplementary Table 4 are depicted as pie graphs in A and D, respectively. B and E: The grade distributions of the CD8+ T-cell epitopes in Table 1 and the 418 CD4+ T-cell epitopes in Table 2 are shown in B and E, respectively. Gray boxes summarize the grading criteria (see Fig. 2). C and F: The antigen sources of the CD8+ T-cell epitopes in Table 1 and the CD4+ T-cell epitopes in Table 2 are depicted as pie graphs in C and F, respectively. Epitopes arising from nonconventional antigens (bottom portions of Tables 1 and 2) are not included. For the eight antigens that are sources of both CD8+ and CD4+ T-cell epitopes (i.e., CHGA, GAD65, IA-2, IAPP, IGRP, INS, S100β, and ZnT8), the same color code is used in C and F.

Figure 3

HLA restriction and grade and antigen distributions for CD8+ and CD4+ T-cell epitopes of β-cell antigens. AC: HLA class I–restricted epitopes. DF: HLA class II–restricted epitopes. A and D: The HLA restrictions for the 142 CD8+ T-cell epitopes in Table 1 and the 143 CD4+ T-cell epitopes in Supplementary Table 4 are depicted as pie graphs in A and D, respectively. B and E: The grade distributions of the CD8+ T-cell epitopes in Table 1 and the 418 CD4+ T-cell epitopes in Table 2 are shown in B and E, respectively. Gray boxes summarize the grading criteria (see Fig. 2). C and F: The antigen sources of the CD8+ T-cell epitopes in Table 1 and the CD4+ T-cell epitopes in Table 2 are depicted as pie graphs in C and F, respectively. Epitopes arising from nonconventional antigens (bottom portions of Tables 1 and 2) are not included. For the eight antigens that are sources of both CD8+ and CD4+ T-cell epitopes (i.e., CHGA, GAD65, IA-2, IAPP, IGRP, INS, S100β, and ZnT8), the same color code is used in C and F.

One conclusion is that the known CD8+ T-cell epitopes provide only limited MHC coverage (Fig. 3A), with the vast majority of identified peptides being recognized in the context of HLA-A*02:01. This discovery bias stems, in large part, from the high prevalence of this allele among the Caucasian population, which is the most frequently studied. In addition, mice transgenic for HLA-A*02:01 have been available for over two decades (17), and many of the CD8+ T-cell epitopes were discovered and/or characterized using this model (Table 1). Despite the fact that HLA-B*39:06 and HLA-A*24:02 are predisposing for type 1 diabetes (11), no type 1 diabetes–related CD8+ T-cell epitopes have been reported for HLA-B*39:06, and only a handful are known for HLA-A*24:02, all derived from INS. For provision of broad population coverage, e.g., for T-cell monitoring efforts, which increasingly rely on peptide-MHC Mmr, epitope discovery that targets alleles other than HLA-A*02:01, especially HLA-B*39:06 and HLA-A*24:02, is a pressing need.

CD4+ T-Cell Antigens and Epitopes

Several lines of evidence support the importance of CD4+ T cells in type 1 diabetes. As mentioned, the disease has an overwhelming genetic association with specific HLA class II haplotypes, implying a role for CD4+ T cells in the disease. In addition, the development of type 1 diabetes is often marked by the presence of multiple islet-specific autoantibodies (18). The appearance of these high-affinity antibodies implies that self-reactive CD4+ T cells are also activated and provide help to autoreactive B cells. Convincing data from the NOD mouse model demonstrate that H2-Ag7–restricted responses to the INS 33–47 (B9–B23) epitope are crucial for disease development in this model (19); T cells that recognize that epitope were shown to be present in patients with recent-onset type 1 diabetes with frequencies that correlated with insulin autoantibody levels (20). Although CD8+ T cells are typically the predominant T-cell population in human insulitis (21), CD4+ T cells are also present within islets and a growing subset of HLA class II–restricted epitope specificities that were originally defined in peripheral blood have been shown to be recognized by islet-resident and pLN-derived T cells (21,22). Furthermore, a recent study (23) confirmed previous reports (24,25) that β-cells from the infiltrated islets of donors with type 1 diabetes express HLA class II on their cell surface, supporting the long-debated possibility of direct interactions between CD4+ T cells and islets.

A formidable number of studies have applied an array of methods and approaches to identify CD4+ T-cell epitopes derived from diabetes-associated antigens (Supplementary Table 2). The earliest of these studies focused on antigens that correspond to the most clearly defined autoantibody targets, i.e., INS, GAD65, and IA-2, and these remain the most extensively studied antigens both in terms of the quantity of individual reports and the number of unique epitopes identified (Table 2 and Fig. 3F). However, additional antigens of interest have emerged over time, including some that were addressed by multiple studies, e.g., ZnT8 and IGRP, and others that are only supported by single references to date, e.g., S100β and heat shock protein 70 (HSP70). We caution that the sizes of the slices in the pie graphs depicted in Fig. 3F (and Fig. 3C also) surely reflect some discovery bias rather than a simple correlation with the importance of each antigen.

A particular challenge for analyzing and compiling CD4+ T-cell epitopes is that the HLA class II binding groove readily accommodates peptides with variable lengths (typically 14–21 amino acids). Studies of the class II immunopeptidome indicate that nested sets of related peptides that share a consensus motif, but which have undergone varying degrees of proteolytic processing, decorate the surface of professional antigen-presenting cells (26). Furthermore, the synthetic peptide sets used for epitope discovery efforts by different groups at different times were designed with different lengths and degrees of overlap, leading to the definition of groups of highly similar peptide epitopes. For example, within GAD65 residues 265–292, seven partially overlapping peptides were defined as DR0401–restricted epitopes (Table 3). However, that segment of GAD65 includes only two plausible DR0401-binding motifs, suggesting that some of these peptides share the same minimal epitope. Thus, in order to graphically summarize the HLA restriction for the CD4+ T-cell epitopes (Fig. 3D) without overcounting the number of epitopes defined for well-studied HLA alleles, we first constructed an HLA-specific epitope table (Supplementary Table 4) in which we grouped “families” of epitopes into single lines. To achieve this, we sorted entries from Table 2 based on HLA, and those with unknown or ambiguous HLA information were excluded. The IEDB epitope prediction tool (http://tools.iedb.org/mhcii/) (5) was then used to define the most likely core nonamer for each epitope. All lines that shared the same HLA restriction and core nonamer were collapsed into a single line. While acknowledging that amino acids flanking the core peptide may influence T-cell recognition (27), we took this approach because failing to do so would likely overestimate the number of epitopes that have been discovered for well-studied alleles such as DR0401.

Table 3

Groups of overlapping DR0401-restricted GAD65 epitope “families”

Reported epitopePeptide sequenceEpitope family AEpitope family B
GAD65 265–284 KGMAALPRLIAFTSEHSHF  
GAD65 266–285 GMAALPRLIAFTSEHSHFSL   
GAD65 270–283 LPRLIAFTSEHSHF (KGMAAL)PRLIAFTSEHSHF(SLKK)  
GAD65 270–287 LPRLIAFTSEHSHFSLK  
GAD65 271–285 PRLIAFTSEHSHFSL   
GAD65 273–292 LIAFTSEHSHFSLKKGAAAL  (LPRL)IAFTSEHSHFSLK(KGAAAL) 
GAD65 274–286 IAFTSEHSHFSLK   
Reported epitopePeptide sequenceEpitope family AEpitope family B
GAD65 265–284 KGMAALPRLIAFTSEHSHF  
GAD65 266–285 GMAALPRLIAFTSEHSHFSL   
GAD65 270–283 LPRLIAFTSEHSHF (KGMAAL)PRLIAFTSEHSHF(SLKK)  
GAD65 270–287 LPRLIAFTSEHSHFSLK  
GAD65 271–285 PRLIAFTSEHSHFSL   
GAD65 273–292 LIAFTSEHSHFSLKKGAAAL  (LPRL)IAFTSEHSHFSLK(KGAAAL) 
GAD65 274–286 IAFTSEHSHFSLK   

Letters in boldface type indicate the amino acids that are shared among epitope family A members. Underlined letters indicate the predicted minimal 9mer for that family. Italicized letters indicate the amino acids that are shared among epitope family B members. Underlined letters indicate the predicted minimal 9mer for that family.

In examination of the HLA class II epitope knowledge accumulated to date, some clear discovery bias is evident. One striking bias is that, even after collapsing of closely related families of epitopes, there is clearly a preferential documentation of HLA-DR4–restricted epitopes (especially the DR0401 subtype) in comparison with HLA-DR3 (Fig. 3D), though both are associated with type 1 diabetes. DQ8 and DQ2 (and the trans-dimers that can form in heterozygous subjects) are also high-risk HLA allotypes, in linkage disequilibrium with DR4 and DR3, respectively. Thus, it is notable that for many antigens, e.g., IGRP and ZnT8, no T-cell epitopes have yet been defined to be recognized in the context of these two HLA molecules or DQ8-trans (α-chain of DQ2 and β-chain of DQ8) and DQ2-trans (α-chain of DQ8 and β-chain of DQ2) (28) (Table 2). In the case of ZnT8, peptide elution and mass spectrometry have suggested some candidates (29). Furthermore, for multiple antigens, including heat shock protein 60 (HSP60), HSP70, and 69-kDa islet cell autoantigen (ICA69), the restricting HLA for all epitopes remains undefined (Table 2). Another crucial gap is the lack of epitope discovery work for the HLA alleles that are associated with susceptibility to type 1 diabetes in non-Caucasian populations, e.g., DRB1*04:05-DQB1*04:01 and DRB1*09:01-DQB1*03:03 in Japanese and Korean populations (30).

CD8+ and CD4+ T-Cell Epitopes: A Common Need to Improve Their Grades

In addition to an HLA bias for both CD8+ and CD4+ T-cell epitopes, another gap that emerges from our analysis is a dearth of epitopes with high levels of evidence (Fig. 3B and E). Returning to our epitope scoring criteria (Fig. 2), 41% and 82% of CD8+ and CD4+ T-cell epitopes, respectively, do not have evidence of natural processing and presentation, relegating these epitopes to the lower strata (grades of C+ or lower) and leaving open the possibility that some of these peptides could be mimotopes rather than disease-associated epitopes. Though beyond the scope of our current efforts, mining of existing (e.g., 31) and future data sets arising from MHC purification followed by peptide elution and sequencing might help to establish natural processing and presentation for some of these epitopes.

Furthermore, while a growing number of specificities have been documented to be present among islet-infiltrating or pLN-derived T cells (8% of the HLA class I–restricted epitopes and 6% of class II), the vast majority of reported epitopes have not, having instead been defined in peripheral blood or HLA-Tg mice (Tables 1 and 2). Although the experimental work required to bridge this knowledge gap is intensive and relies on precious source material, determining which T-cell specificities are found in disease-proximal tissues will be crucial for our understanding of the disease (32).

Despite these limitations, 4 of 142 HLA class I–restricted epitopes earned grades of A+: GAD65 114–123, INS 15–24 (L15–L24), INS 34–42 (B10–B18), and ZnT8 186–194, all recognized by T cells in the context of HLA-A*02:01 (Table 1). Also, 3 of 418 class II–restricted epitopes scored as A+: GAD65 115–127 (DR0401), GAD65 274–286 (DR0401), and INS 33–47 (B9–23) (DQ8). It is noteworthy that, in two instances, there is overlap between the A+ class I and class II epitopes: GAD65 114–123/115–127 and INS 34–42/33–47 (B10–B18/B9–B23).

Emerging Neo-epitopes

In the context of type 1 diabetes, neo-epitopes were first defined as those generated by posttranslational modification of a DNA-encoded antigen, with the first reported modified epitope including an atypical vicinal disulfide modification of insulin and recognized by CD4+ T cells (33). Subsequent reports have highlighted additional mechanisms of epitope modification for both CD8+ and CD4+ T cells, including enzymatic citrullination (by peptidylarginine deiminase enzymes) and deamidation (by tissue transglutaminase) of self-proteins, which are reported to be triggered by endoplasmic reticulum stress in β-cells (3437). The term “neo-epitopes” has more recently begun to be used to encompass other nonconventional epitopes. In the case of CD4+ T cells, these include hybrid insulin peptides (HIPs) that may form within β-cell secretory granules and consist of amino acid stretches from INS and a second protein or a noncontiguous segment of INS (38,39). For CD8+ T cells, other nonconventional epitopes include those derived from alternative splicing products (31) or defective ribosomal products (40) and hybrid epitopes potentially resulting from proteasomal splicing of two different regions of a protein (or proteins) (31). The universe of neo-epitopes represents a rapidly developing area of discovery. These developments complicate the landscape of antigens and epitopes but also reveal new mechanisms that may contribute to disease. Posttranslationally modified epitopes are included with conventional ones in Tables 1 and 2, with the posttranslational modifications indicated; other nonconventional epitopes are listed in a separate section of each table.

Discrimination Between Patients With Type 1 Diabetes and Control Subjects

Many studies have compared the ex vivo frequencies of circulating islet-reactive T cells between patients with type 1 diabetes and control subjects. This information is provided in the “Ex vivo type 1 diabetes > controls” columns of Supplementary Tables 1 and 2, in which we evaluated each epitope as enriched (or not) in patients with type 1 diabetes compared with control subjects—but only when this comparison was statistically supported. The control subjects used for nearly all of the studies were healthy donors, as opposed to first-degree relatives of patients with type 1 diabetes. Occasionally, patients with type 2 diabetes were used as control subjects. Overall, for CD8+ T cells, several studies are concordant at detecting a frequency difference between donors with type 1 diabetes and control donors for different epitopes when using a functional readout, most often an interferon (IFN)-γ ELISpot assay, for example (41). It is, however, noted that several publications failed to provide statistical evidence, either because they were underpowered or because they did not report statistical analyses. For CD4+ T cells, some consensus exists also when nonfunctional HLA class II Mmr assays were used. The agreement is less unanimous for CD8+ T cells detected by HLA class I (mostly HLA-A2) Mmr assays. Indeed, Mmr+CD8+ T cells were often (14,31,42,43), but not invariably (44,45), found at similar frequencies in the peripheral blood of individuals with type 1 diabetes and healthy individuals and have been variably reported to harbor more differentiated effector/memory phenotype in patients with type 1 diabetes (14,44), or a largely naive phenotype irrespective of disease status (31,42). Some islet-reactive CD8+ T cells that did not exhibit frequency differences between donors with type 1 diabetes and healthy donors in blood were enriched in the pancreas of donors with type 1 diabetes, suggesting that the fraction actively involved in disease may undergo preferential homing to the target organ (31,42).

Collectively, regarding the discrimination between patients with type 1 diabetes and control subjects, four matters emerge from our analysis. First, different findings were obtained when detecting T cells, notably CD8+ T cells, with functional ELISpot assays versus Mmr assays, which may reflect bystander activation or regulatory mechanisms at play in functional assays or a greater sensitivity of functional readouts for detecting low-avidity T cells (46). Second, large variations in the reported frequencies of T cells reactive to the same epitope are noted (likely due in part to different methods and/or variable reagent quality). These variations argue for a pressing need to reach a consensus on more stringent criteria to report T-cell frequencies and phenotype distributions, e.g., avoiding the potential bias of undersampling for these rare populations. Some of the challenges accompanying the standardization of T-cell biomarkers in type 1 diabetes have recently been reviewed (47). Third, different degrees of “benign” islet T-cell autoimmunity (42) seem to exist in individuals without diabetes, calling for efforts to define the features that shape the progression of this sometimes temporary benign state toward type 1 diabetes. Fourth, the analysis of more disease-proximal tissues, i.e., the pancreas and pLNs, adds important information and should be increasingly implemented (32).

Knowledge Gaps and Unmet Needs

Major progress has been made in the past several years to define the target epitopes of islet-reactive T cells (Fig. 1). Besides the obvious merits of improving our understanding of type 1 diabetes pathogenesis, these efforts should continue in order to provide a comprehensive coverage of the overall autoimmune T-cell repertoire of a given individual. It is well established that the detection of multiple autoantibodies, as opposed to a single one, is more predictive of subsequent progression toward clinical type 1 diabetes (stage 3 [48]). Similarly, we may expect that analyzing autoreactive T cells recognizing more antigens rather than just a few may provide better prognostic stratification. In this respect, it will be critical to expand not only the panel of validated epitopes but also their HLA restrictions, as most epitopes already identified are restricted by HLA-A2 or -DR0401 (Fig. 3A and D). Other points for future improvement will be to increase the number of epitopes featuring an A+ level of evidence, as they are still too few at present, and to explore the utility of CD4+ versus CD8+ T-cell biomarkers (or combinations thereof) according to the application envisaged, as they may provide different and possibly complementary information. We recognize that periodic updates to the information presented here will be needed in the future, not only to add the epitopes that continue to be discovered, but also potentially to revise the epitope grading rubric based on advances in the field. For example, results from the clinic might also be considered for scoring in the future, e.g., the usefulness of an epitope in predicting disease, in measuring progression, or as a peptide therapeutic.

A novel view of type 1 diabetes as a disease continuum starting with β-cell autoimmunity, most commonly measured by autoantibody appearance, has been endorsed by the diabetes community (48). The corollary to this view is that type 1 diabetes prevention efforts should ideally target the underlying, early islet autoimmunity rather than its late consequence, i.e., hyperglycemia. This calls for novel biomarkers—including T-cell biomarkers—that may appear before autoantibodies and predict subsequent seroconversion and disease progression (49). The finding that less than half of patients with diabetes induced by immune checkpoint inhibitors have autoantibodies to GAD65, INS, IA-2, or ZnT8 supports the view that autoantibodies may be a consequence of islet autoimmunity rather than its first manifestation (50). A caveat to this reasoning is that checkpoint inhibitor diabetes remains a new and poorly characterized disease entity; it is possible that the antigens targeted by autoantibodies (and T cells) will differ from the usual suspects. Indeed, like the rare individuals who develop type 1 diabetes despite having protective HLA alleles (51), patients with checkpoint inhibitor diabetes may also offer new insights into important autoantigens in type 1 diabetes and/or alternative pathways of disease development.

The aforementioned knowledge gap about the differential features of islet-reactive T cells between the type 1 diabetes and healthy states (and anywhere in between) will be a priority area for future research. Indeed, defining the molecular switch between “benign” and progressive islet autoimmunity may provide the earliest biomarkers for type 1 diabetes staging and, possibly, new therapeutic targets to maintain or restore the benign state. In this regard, the scarcity of studies analyzing T-cell biomarkers in preclinical, stage 1–2, type 1 diabetes reveals another area for improvement. As many therapeutic strategies target T cells, T cell–based biomarkers are also expected to improve the selection of patients to enroll in clinical trials and their immune monitoring after treatment. Our update and reappraisal of the current state of knowledge regarding the T-cell epitopes of potential relevance to type 1 diabetes should help in the forwarding of each of these objectives.

E.A.J. and R.M. contributed equally to this work.

This article contains supplementary material online at https://doi.org/10.2337/figshare.12179796.

Acknowledgments. The authors thank Nima Salimi (IEDB) for assistance with epitope data curation and for working with IEDB staff to ensure that all of the epitopes in this article were assigned identification numbers. The authors appreciate the Immunology of Diabetes Society T Cell Workshop for fostering discussions that launched this epitope reappraisal.

Funding. Work in the laboratory of E.A.J. is supported by grants from JDRF (1-SRA-2017-344-S-B and 2-SRA-2018-551-S-B). Work in the laboratory of R.M. is supported by grants from JDRF (2-SRA-2016-164-Q-R), The Leona M. and Harry B. Helmsley Charitable Trust (1901-03689), Fondation Francophone pour la Recherche sur le Diabète, Agence Nationale de la Recherche (ANR-19-CE15-0014-01), Fondation pour la Recherche Médicale (EQU20193007831), and the Innovative Medicines Initiative 2 Joint Undertaking (INNODIA, 115797), which receives support from the EU Horizon 2020 program, the European Federation of Pharmaceutical Industries and Associations, JDRF, and The Leona M. and Harry B. Helmsley Charitable Trust. Work in the laboratory of S.C.K. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (UC4 DK116284). S.C.K. is the George F. and Sybil H. Fuller Term Chair in Diabetes. Work in the laboratory of T.P.D. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK120420 and P30 DK020541, which supports the Einstein–Mount Sinai Diabetes Research Center), the National Institute of Allergy and Infectious Diseases (R01 AI123730), and the American Diabetes Association (1-16-IBS-069). T.P.D. is the Diane Belfer, Cypres & Endelson Families Faculty Scholar in Diabetes Research.

Duality of Interest. R.M. holds patents related to some of the antigens reviewed here. No other potential conflicts of interest relevant to this article were reported.

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