White_2024_Front.Immunol_15_1444639

INTRODUCTION: We reported that Ca(2+)-independent phospholipase A(2)beta (iPLA(2)beta)-derived lipids (iDLs) contribute to type 1 diabetes (T1D) onset. As CD4(+) and CD8(+) T cells are critical in promoting beta-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)beta(+/-) (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 beta-cells. Reduced iPLA(2)beta 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%) IFNgamma(+)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.