Dietary Reversal of Dyslipidemia Ameliorates CD1b-Autoreactive T Cell-Mediated Skin Inflammation 2257438

Abstract Introduction Unconventional group 1 CD1 (CD1a, b, and c)-restricted T cells recognize self/microbial lipid antigens and play important roles in autoimmunity and host defense. Dyslipidemia, characterized by abnormal plasma lipid levels, can modulate conventional T cell responses by altering their metabolism and effector functions. We hypothesis that dyslipidemia may also affect the function of CD1-restricted self-lipid-reactive T cells through changes in the quantity and quality of various lipid species. Methods We utilized a double-transgenic mouse model expressing human group 1 CD1 and CD1b-restricted autoreactive TCR (HJ11Tg) on a Rag-deficient and LDL receptor (LDLR)-deficient background (HJ1Tg/hCD1Tg/Rag-/-/LDLR-/-) to investigate the impact of diet-induced dyslipidemia on CD1b-autoreactive T cells. Mice were fed either a normal chow (NC) or a high fat diet (HFD) for eight weeks. In the diet-switch group, HFD-fed mice were returned to NC for an additional three weeks. Results Diet-induced dyslipidemia markedly enhanced HJ1 T cell activation, proliferation, IL-17A production, leading to neutrophil-mediated skin inflammation. Switching from HFD to NC significantly alleviated skin inflammation, accompanied by reduced HJ1 T cell activation, proliferation, and IL-17A-driven neutrophil infiltration. RNA-seq analysis of skin tissues revealed up-regulation of genes associated with inflammation, neutrophil chemotaxis, cell cycle, and wound healing in HFD-fed mice, as compared with NC and diet-switch groups. Conclusion These findings demonstrate that CD1b-restricted autoreactive T cells mediate a reversible, lipid-driven skin pathology, highlighting the dynamic link between dyslipidemia and immune regulation. Funding Source NIH grants R01 AI057460 and R01 AI180031 Topic Categories Basic Autoimmunity (BA)