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 T_H17 and its balance with regulatory T cell (T_reg) generation is closely related to autoimmune pathogenesis. The roles of RNA-RBP interaction in regulation of T_H17/T_reg differentiation and autoinflammation remain in need of further investigation. Here we report that lncRNA-GM polarizes T_H17 differentiation but inhibits iT_reg differentiation by reducing activity of Foxo1, a transcriptional factor that is important in inhibiting T_H17 differentiation but promoting T_reg generation. <i>lncRNA-GM</i>-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 <i>Il23r</i> transcription. The human homolog of lncRNA-GM (AK026392.1) also polarizes human T_H17 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.