112-OR: Adoptive Transfer of CD4+ T Cells with Reduced iPLA2b Expression Mitigates T1D Development Free

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 lipid signaling plays in this process. We find that the Ca²⁺-independent phospholipase A₂β (iPLA₂β) is induced under a diabetic milieu and mitigation of iPLA₂β activity attenuates β-cell death. iPLA₂β, a member of the PLA₂ family, 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 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 by utilizing a splenocyte adoptive transfer protocol. Our findings suggested that reduced iPLA₂β expression in splenocytes: (1) delayed T1D incidence, (2) improved glucose homeostasis and (3) reduced the production of iDLs. To further elucidate the link between iPLA₂ expression and T lymphocytes in T1D progression, we investigated the role of T-cell derived iDLs by utilizing combinations of T-cell transfers. We isolated CD4⁺/8⁺ T-cells from splenocytes prepared from 6-week-old donor NOD and NOD iPLA₂β^+/- (NOD.HET). These were transferred to 4-week-old immunodeficient NOD.scid recipient mice. We find that: (1) WT4/8 recipient mice develop T1D between 14-16 weeks of age. In contrast, T1D onset in HET4/8 recipient mice is delayed by 16 weeks, (2) temporal IPGTTs reveal that recipient mice of HET4/8 T-cells were more glucose tolerant, compared to recipients of the WT4/8 T-cells, (3) reduced iPLA₂β expression in CD4 T cells proved to be effective in delaying T1D progression, and (4) HET donor T-cell production of select pro-inflammatory iDLs is decreased. These findings suggest that iPLA₂β in CD4 T-cells is a critical contributor to the production of pro-inflammatory iDLs and could be a potential target in reducing T1D development.