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=Volume 15 - 2024

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=We reported that Ca2+-independent phospholipase A2β (iPLA2)-derived lipids (iDLs) contribute to T1D onset. As CD4+ and CD8+ T-cells are critical in promoting -cell death, we tested the hypothesis that iDL signaling from these cells participate in T1D development. To address this, CD4+ and CD8+ T-cells from wild type non-obese diabetic (NOD) and NOD.iPLA2+/- (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 -cells. Reduced iPLA2 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%) IFN+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.