AUTHOR=White Tayleur D. , Almutairi Abdulaziz , Gai-Tusing Ying , Stephenson Daniel J. , Stephenson Benjamin D. , Chalfant Charles E. , Lei Xiaoyong , Lu Brian , Hammock Bruce D. , DiLorenzo Teresa P. , Ramanadham Sasanka 

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

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1444639

DOI=10.3389/fimmu.2024.1444639

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><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></sec><sec><title>Methods</title><p>CD4<sup>+</sup> and CD8<sup>+</sup> T cells from wild-type non-obese diabetic (<italic>NOD</italic>) and <italic>NOD</italic>.<italic>iPLA<sub>2</sub>β<sup>+/-</sup></italic> (NOD<italic>.HET</italic>) mice were administered in different combinations to immunodeficient NOD.<italic>scid</italic>. </p></sec><sec><title>Results</title><p>In mice receiving only <italic>NOD</italic> 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<italic>.HET</italic> 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 <italic>sEH</italic> and <italic>granzyme B</italic>. </p></sec><sec><title>Discussion</title><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></sec>