74-OR: Adoptively Transferred T Lymphocytes with Reduced iPLA2b Expression Delays Type 1 Diabetes Development in NOD Mice 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 T-cell adoptive transfer. We isolated CD4⁺/8⁺ T-cells from splenocytes prepared from 11-week-old donor female NOD and NOD.iPLA₂ β ^+/- (HET) . These were transferred i.p. to 4-week-old NOD.scid recipient mice. We find that NOD4/8-recipient mice develop T1D between 14-16 weeks of age. In contrast, T1D onset in HET4/8-recipient mice is delayed by 12 weeks and this was associated with better glucose tolerance, compared to NOD4/8 T-cell recipients. This finding is also supported by histology analysis of the pancreatic islet, which revealed less islet infiltration, more islet abundance, and the frequency of CD4 T cells were increased in the pancreas of HET4/8-recipient mice compared to NOD4/8 recipients. Further, lipidomics analyses revealed that HET donor T-cell production of proinflammatory lipids (i.e., PGE₂ and DHETs) is decreased, relative to NOD T-cells. These findings suggest that pro-inflammatory iDLs generated by CD4 T-cells are critical contributors T1D development and can be targeted to counter T1D onset.