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. 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 _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.

Abstract

Abstract

LncRNA-GM promotes T _H17 differentiation but inhibits T _reg generation to exacerbate autoimmune inflammation by targeting Foxo1.