1667-P: Diabetes Incidence following Adoptive Transfer of Splenocytes Correlates with Increased Generation of Proinflammatory Lipids

Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease characterized by the destruction of insulin-producing pancreatic islet β-cells. An understudied area is the role of lipid signaling. We find that the Ca²⁺-independent phospholipase A₂β (iPLA₂β) is induced under a diabetic milieu and that mitigation of iPLA₂β activity attenuates β-cell death. iPLA₂β hydrolyzes the sn-2 substituent from glycerophospholipid substrates to yield a free fatty acid. When the fatty acid is arachidonic acid, it can be metabolized to bioactive eicosanoids, many of which are pro-inflammatory. To address our overarching hypothesis that iPLA₂β-derived lipids (iDLs) contribute to T1D development, we investigated the role of immune cell-iDLs in this process by utilizing a splenocyte adoptive transfer protocol. Splenocytes were prepared from 12-week-old female spontaneous diabetes prone non-obese diabetic (NOD, WT) and NOD.iPLA₂β^+/- (HET) donor mice and transferred into 5-week-old female immunodeficient (NOD.scid) recipient mice. Our overall findings revealed that: (1) splenocyte-iPLA₂β mRNA in HET donor mice was ca. 40% of that in WT donor mice, (2) temporal IPGTTs revealed that the recipient mice of the HET genotype were more glucose tolerant, compared to recipients of the WT splenocytes; (3) weekly blood glucose monitoring revealed that all WT recipient mice developed diabetes between 11-16 weeks of age. In contrast, onset of diabetes in the HET recipient mice was delayed 3 weeks and by 16 weeks of age, 50% of these mice remained diabetes-free, (4) HET donor T-cell differentiation to Th1 phenotype is mitigated, (5) HET donor T-cell production of select pro-inflammatory lipids (i.e., 6-keto PGF₁α, PGE₂, and DHETs) is decreased, relative to WT donors, and (5) similar lipid signatures are evident in the terminal plasma of recipient mice. These findings suggest that immune T-cell-iPLA₂β is a critical contributor to T1D development and could be targeted for therapeutics.