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

RNA-RBP interaction is important in immune regulation and implicated in various immune disorders. The differentiation of proinflammatory T cell subset T(H)17 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(H)17/T(reg) differentiation and autoinflammation remain in need of further investigation. Here we report that lncRNA-GM polarizes T(H)17 differentiation but inhibits iT(reg) differentiation by reducing activity of Foxo1, a transcriptional factor that is important in inhibiting T(H)17 differentiation but promoting T(reg) 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 T(H)17 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.