Arid5a stabilizes OX40 mRNA in murine CD4+ T cells by recognizing a stem-loop structure in its 3'UTR

Abstract

AT-rich interactive domain-containing protein 5a (Arid5a) is an RNA-binding protein (RBP) required for autoimmunity via stabilization of interleukin-6 (Il6) and signal transducer and activator of transcription 3 (STAT3) mRNAs. However, the roles of Arid5a in Th17 cells and its association with autoimmunity remains unknown. Here, we show that the levels of Arid5a and OX40 are correlated in CD4⁺ T cells under Th17 conditions in an IL-6-dependent manner. Lack of Arid5a in T cells reduced OX40 expression levels and repressed IL-17 production in response to OX40 ligation. Arid5a stabilized OX40 mRNA by recognizing the alternative decay element (ADE)-like stem-loop (SL) in the 3' untranslated region (3'UTR). Interestingly, Arid5a impaired the RNA-destabilizing functions of Regnase-1 and Roquin-1 on OX40 ADE-like SL. In experimental autoimmune encephalomyelitis (EAE), Arid5a-deficient mice exhibited resistance to EAE, with reduced OX40 expression in CD4⁺ T cells, and the number of CD4⁺CD45⁺ T cells was decreased in central nervous system (CNS). Furthermore, ameliorated EAE was induced by adoptive transfer of Arid5a^−/− encephalitogenic CD4⁺ T cells expressing less OX40 mRNA and producing less IL-17. In conclusion, our findings indicate that the Arid5a/OX40 axis in CD4⁺ T cells may have important implications in pathogenesis of autoimmune diseases such as EAE.

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