Presentation1_Differential lipid signaling from CD4+ and CD8+ T cells contributes to type 1 diabetes development.pptx

Introduction<p>We reported that Ca<sup>2+</sup>-independent phospholipase A<sub>2</sub>β (iPLA<sub>2</sub>β)–derived lipids (iDLs) contribute to type 1 diabetes (T1D) onset. As CD4<sup>+</sup> and CD8<sup>+</sup> T cells are critical in promoting β-cell death, we tested the hypothesis that iDL signaling from these cells participates in T1D development. </p>Methods<p>CD4<sup>+</sup> and CD8<sup>+</sup> T cells from wild-type non-obese diabetic (NOD) and NOD.iPLA<sub>2</sub>β<sup>+/-</sup> (NOD.HET) mice were administered in different combinations to immunodeficient NOD.scid. </p>Results<p>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<sub>2</sub>β led to decreased production of proinflammatory lipids from CD4<sup>+</sup> T cells including prostaglandins and dihydroxyeicosatrienoic acids (DHETs), products of soluble epoxide hydrolase (sEH), and inhibition of their signaling decreased (by 82%) IFNγ<sup>+</sup>CD4<sup>+</sup> cells abundance. However, only DHETs production was reduced from CD8<sup>+</sup> T cells and was accompanied by decreases in sEH and granzyme B. </p>Discussion<p>These findings suggest that differential select iDL signaling in CD4<sup>+</sup> and CD8<sup>+</sup> T cells contributes to T1D development, and that therapeutics targeting such signaling might be considered to counter T1D.</p>