Regulation of RORγt in inflammatory lymphoid cell differentiation

Abstract

T-helper 17 (Th17) cells differentiate from naive CD4+ T cells in response to signals from commensal microbiota and produce cytokines critical for the integrity of mucosal barriers. These cells also disseminate throughout the body, and are key participants in numerous inflammatory processes. A key challenge is to elucidate the mechanisms that govern Th17 cell beneficial versus pathogenic functions, characterized by different cytokine profiles. Mucosal Th17 cells require the nuclear hormone receptor RORγ for their differentiation in draining lymph nodes. Cytokine expression is enabled in select tissues, to which these cells migrate, by external cues, such as the serum amyloid A proteins produced in response to commensal bacteria by epithelial cells in the small intestine. Additional cell-intrinsic cues contributing to production of Th17 cytokines during both homeostasis and inflammation include the RORγ-associated DEAD-box RNA helicase DDX5 and long noncoding RNA (lncRNA) Rmrp. The helicase activity of DDX5 is required for Rmrp-mediated assembly of the complex and colocalization with RORγ throughout the genome to regulate key Th17 genes. How these are regulated in diverse microenvironments may provide insights for therapeutic intervention in autoimmune disease.