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

Yali Chen; Juan Liu; Xiaomin Zhang; Ha Zhu; Yujia Wang; Zhiqing Li; Yanfang Liu; Shuo Liu; Shuxun Liu; Nan Li; Kun Chen; Xuetao Cao

doi:10.1126/sciadv.abn9181

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

Sci Adv. 2022 Aug 5;8(31):eabn9181. doi: 10.1126/sciadv.abn9181. Epub 2022 Aug 5.

Authors

Yali Chen^{1

2}, Juan Liu², Xiaomin Zhang², Ha Zhu², Yujia Wang³, Zhiqing Li², Yanfang Liu², Shuo Liu³, Shuxun Liu², Nan Li², Kun Chen^{3

4}, Xuetao Cao^{1

2

3

5}

Affiliations

¹ Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
² National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
³ Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China.
⁴ Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China.
⁵ Frontier Research Center for Cell Response, Institute of Immunology, College of Life Sciences, Nankai University, Tianjin 300071, China.

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.