lncRNA-GM targets Foxo1 to promote T cell-mediated autoimmunity

Abstract

RNA-RBP interaction is important in immune regulation and implicated in various immune disorders. The differentiation of proinflammatory T cell subset TH17 and its balance with regulatory T cell (Treg) generation is closely related to autoimmune pathogenesis. The roles of RNA-RBP interaction in regulation of TH17/Treg differentiation and autoinflammation remain in need of further investigation. Here we report that lncRNA-GM polarizes TH17 differentiation but inhibits iTreg differentiation by reducing activity of Foxo1, a transcriptional factor that is important in inhibiting TH17 differentiation but promoting Treg generation. lncRNA-GM-deficient mice were protected from experimental autoimmune encephalomyelitis. Mechanistically, lncRNA-GM directly binds to cytoplasmic Foxo1, thus inhibiting its activity through blocking dephosphorylation of Foxo1 by phosphatase PP2A to promote Il23r transcription. The human homolog of lncRNA-GM (AK026392.1) also polarizes human TH17 differentiation. Our study provides mechanistic insight into the interaction of lncRNA and transcriptional factor in determining T cell subset differentiation during T cell-mediated autoimmune diseases.