Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR–S6K pathway

TLDR

Microbial metabolites such as short‑chain fatty acids (SCFAs) are abundant in the intestine and may regulate the immune system. The study examined how SCFAs influence T‑cell differentiation into effector and regulatory subsets. SCFAs inhibit histone deacetylases, increasing acetylation of p70 S6 kinase and phosphorylation of rS6, thereby activating the mTOR pathway that drives Th17, Th1, and IL‑10⁺ T‑cell generation. SCFAs directly promote differentiation of T cells into IL‑17, IFN‑γ, or IL‑10‑producing cells independent of GPR41/43, with acetate enhancing Th1/Th17 responses during Citrobacter rodentium infection while reducing anti‑CD3‑induced inflammation in an IL‑10‑dependent manner, illustrating that SCFAs can drive both immunity and tolerance depending on the cytokine milieu.

Abstract

Microbial metabolites, such as short-chain fatty acids (SCFAs), are highly produced in the intestine and potentially regulate the immune system. We studied the function of SCFAs in the regulation of T-cell differentiation into effector and regulatory T cells. We report that SCFAs can directly promote T-cell differentiation into T cells producing interleukin-17 (IL-17), interferon-γ, and/or IL-10 depending on cytokine milieu. This effect of SCFAs on T cells is independent of GPR41 or GPR43, but dependent on direct histone deacetylase (HDAC) inhibitor activity. Inhibition of HDACs in T cells by SCFAs increased the acetylation of p70 S6 kinase and phosphorylation rS6, regulating the mTOR pathway required for generation of Th17 (T helper type 17), Th1, and IL-10(+) T cells. Acetate (C2) administration enhanced the induction of Th1 and Th17 cells during Citrobacter rodentium infection, but decreased anti-CD3-induced inflammation in an IL-10-dependent manner. Our results indicate that SCFAs promote T-cell differentiation into both effector and regulatory T cells to promote either immunity or immune tolerance depending on immunological milieu.