Differential lipid signaling from CD4+ and CD8+ T cells contributes to type 1 diabetes development

Introduction We reported that Ca 2+ -independent phospholipase A 2 β (iPLA 2 β)–derived lipids (iDLs) contribute to type 1 diabetes (T1D) onset. As CD4 + and CD8 + T cells are critical in promoting β-cell death, we tested the hypothesis that iDL signaling from these cells participates in T1D development. Methods CD4 + and CD8 + T cells from wild-type non-obese diabetic ( NOD ) and NOD . iPLA 2 β +/- (NOD .HET ) mice were administered in different combinations to immunodeficient NOD. scid . Results In mice receiving only NOD T cells, T1D onset was rapid (5 weeks), incidence 100% by 20 weeks, and islets absent. In contrast, onset was delayed 1 week and incidence reduced 40%–50% in mice receiving combinations that included NOD .HET T cells. Consistently, islets from these non-diabetic mice were devoid of infiltrate and contained insulin-positive β-cells. Reduced iPLA 2 β led to decreased production of proinflammatory lipids from CD4 + T cells including prostaglandins and dihydroxyeicosatrienoic acids (DHETs), products of soluble epoxide hydrolase (sEH), and inhibition of their signaling decreased (by 82%) IFNγ + CD4 + cells abundance. However, only DHETs production was reduced from CD8 + T cells and was accompanied by decreases in sEH and granzyme B . Discussion These findings suggest that differential select iDL signaling in CD4 + and CD8 + T cells contributes to T1D development, and that therapeutics targeting such signaling might be considered to counter T1D.