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

We reported that Ca²⁺-independent phospholipase A₂β (iPLA₂β)-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.

CD4⁺ and CD8⁺ T cells from wild-type non-obese diabetic (NOD) and NOD.iPLA₂β^+/- (NOD.HET) mice were administered in different combinations to immunodeficient NOD.scid.

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 iPLA₂β 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.

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.