Abstract FOXP3 + regulatory T cells (Tregs) are key for immune homeostasis. Tregs are a heterogenous population, however mechanisms regulating their transition from naïve to effector Tregs (eTregs) are poorly understood. Here, we reveal a novel role for nuclear receptor corepressor 1 (NCOR1) in effector Tregs (eTregs). NCOR1 represses an effector signature in naïve Tregs and NCOR1-deficiency increases the fraction of eTregs at steady-state accompanied with an upregulation of cholesterol biosynthesis pathways. Mechanistically, NCOR1-deficiency in murine and human Tregs results in enhanced expression of MYC, an essential driver of eTreg differentiation, resulting in enrichment of MYC target genes. Disruption of the interaction of liver X receptors (LXRs), crucial regulators of cholesterol biosynthesis, with NCOR1 by an LXR agonist leads to increased MYC expression in in vitro generated WT Tregs. Functionally, NCOR1 deficiency in Tregs compromises their ability to protect mice from severe weight loss and intestinal inflammation in adoptive CD4 + T cell transfer colitis. Our data uncover that an LXR-NCOR1 axis regulates eTreg differentiation, and that NCOR1 restrains MYC expression and eTreg differentiation and positively controls effector functions of Tregs.

Nuclear receptor corepressor 1 controls regulatory T cell subset differentiation and effector function