Deficiency of microRNA-10a in CD4+ T cells protects against intestinal infection through mitochondrial oxidation–IL-22 pathway

Abstract Interleukin 22 (IL-22) produced by CD4+ T cells plays an important role in regulating intestinal immune responses during inflammation and infection, but the mechanisms controlling IL-22 expression in T cells remain incompletely understood. MicroRNA-10a (miR-10a) is known to regulate CD4+ T-cell function, but its role in IL-22 production has not been defined. Here, using mouse CD4+ T cell–specific miR-10a knockout models, we examined how miR-10a regulates IL-22 expression and the underlying metabolic mechanisms. MiR-10a deficiency led to increased IL-22 production in CD4+ T cells both in vitro and in vivo, under steady and inflammatory conditions. CD4+ T cell–specific miR-10a knockout mice were resistant to Citrobacter rodentium infection, and the protection was abolished when blocking the IL-22 pathway in mice. Mechanistically, miR-10a–deficient CD4+ T cells exhibited increased mitochondrial oxidative metabolism and membrane potential. Pharmacologic inhibition of mitochondrial complex III with antimycin A suppressed the enhanced IL-22 production in miR-10a–deficient T cells. We further identified Uqcrq, a subunit of mitochondrial complex III, as a direct target of miR-10a, and loss of Uqcrq suppressed IL-22 production in CD4+ T cells. Together, these findings identify miR-10a as a T cell–intrinsic regulator of mitochondrial oxidative metabolism that constrains IL-22 production in the intestine.