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

INTRODUCTION

We reported that Ca-independent phospholipase Aβ (iPLAβ)-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 () and . (NOD) mice were administered in different combinations to immunodeficient NOD..

RESULTS

In mice receiving only 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 T cells. Consistently, islets from these non-diabetic mice were devoid of infiltrate and contained insulin-positive β-cells. Reduced iPLAβ 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%) IFNγCD4 cells abundance. However, only DHETs production was reduced from CD8 T cells and was accompanied by decreases in and .

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.