Acsbg1 regulates differentiation and inflammatory properties of CD4+ T cells

Abstract Epigenetic modifications are critical for the regulation of CD4 + T cell differentiation and function. Previously, we identified Acyl-CoA Synthetase Bubble Gum 1 ( Acsbg1 ), a gene involved in fatty acid metabolism, as part of an epigenetic signature that was selectively demethylated in ex vivo isolated T helper 17 (T H17 ) cells. However, its functional relevance for CD4 + T cells remains incompletely understood. Here, we used in vitro differentiation assays and the adoptive transfer colitis model to investigate the role of Acsbg1 in the differentiation and function of T H1 , T H17 , and regulatory T (T reg ) cells. In vitro , Acsbg1 was expressed in both T H17 and in vitro -induced T reg (iT reg ) cells, whereas T H1 cells lacked Acsbg1 expression. Accordingly, Acsbg1 deficiency resulted in impaired T H17 and iT reg differentiation, whereas T H1 differentiation was unaffected. In vivo , upon adoptive transfer of Acsbg1 ⁻/⁻ T naïve cells, immunodeficient recipient mice exhibited an exacerbated colitis, characterized by an altered balance of T H17 and T reg cells, indicating that Acsbg1 expression is essential for optimal T H17 and T reg cell differentiation and function. Our findings highlight the importance of fatty acid (FA) metabolism in maintaining immune homeostasis by regulating T cell differentiation and provide novel insights into the metabolic targeting of inflammatory diseases.