The T cell receptor (TCR) is a central regulator of the adaptive immune system. Efficient structural organization and signaling of TCR/CD3 underlies the development and function of T cells. T cell maturation defects are associated with autoimmunity, suggesting an underlying defect in TCR selection. To explore quantitative defects as a cause for altered TCR selection at the level of the TCR/CD3 protein complex, we compared TCR expression densities on CD4 T cells from subjects with type 1 diabetes (T1D) (n=80) and nondiabetes controls (n=37) . We also investigated a quantitative defect in genes in the TCR/CD3 genome for possible underlying overmethylation in T1D. All 13 gene regions of the TCR segments and all 4 versions of CD3 proteins were studied for methylation and protein differences in T1D vs. controls. Significant quantitative defects in TCR and CD3 proteins were observed in CD4+ T cells of patients with T1D vs. controls. As a cause for these defects, the TCR complex genes and associated CD3 genes were overmethylated, resulting in downregulated cell surface expression. Evaluation of TCRαβ expression in CD4+ T cells at the protein level confirmed methylation patterns, showing that the population of TCRαβ+ cells was significantly reduced in T1D vs. controls (p=0.005) . The MFI density of TCRαβ antibody in T1D was also significantly decreased vs. controls (p=0.01) . All CD3 genes except CD3ε had hypermethylated patterns in T1D, confirmed by RNAseq analysis. The percentage CD3+ T cells in the CD4+ T cell population was reduced in T1D vs. controls (p=0.04) , as was the MFI of CD3+ T cells (p=0.02) . Patients with T1D have quantitative defects in the TCR/CD3 protein complex, resulting in decreased expression. It is recognized that TCR triggering is affected by intermolecular distance between TCR proteins and that activation diminishes when proximity is increased between TCR surface proteins. In T1D, this might be a novel mechanism for failed T cell selection leading to autoimmunity.
W.Kuhtreiber: None. A.H.Lee: None. A.Aristarkhova: None. H.F.Dias: None. N.Ng: None. S.A.Bien: Employee; Adaptive Biotechnologies. D.L.Faustman: None.