Background:CD4+T cells play an important role in body development and homeostasis. Quantitative and functional changes in CD4+T cells result in abnormal immune responses, which lead to inflammation, cancer, or autoimmune diseases, such as multiple sclerosis (MS). Ubiquitination plays an essential role in the differentiation and functioning of CD4+T cells. However, the function of several E3 ubiquitin ligases in CD4+T cell differentiation and T cell-mediated pathological diseases remains unclear.Methods:RNA sequencing data were analyzed to identify the E3 ubiquitin ligases that participate in the pathogenesis of MS. Furthermore, conditional knockout mice were generated. Specifically, flow cytometry, qPCR, western blot, CO-IP and cell transfer adoptive experiments were performed.Results:In this study, we identified The RING finger 157 (RNF157) as a vital regulator of CD4+T cell differentiation; it promoted Th1 differentiation but attenuated Th17 differentiation and CCR4 and CXCR3 expressions in CD4+T cells, thereby limiting experimental autoimmune encephalomyelitis development. Mechanistically, RNF157 in CD4+T cells targeted HDAC1 for K48-linked ubiquitination and degradation. Notably, RNF157 expression was significantly decreased and showed a significant negative correlation with RORγt expression in patients with MS.Conclusions:Our study highlights the critical role of RNF157 in regulating CD4+T cell functions in autoimmune diseases and suggests RNF157 as a potential target in adaptive immune responses against MS and other autoimmune disorders.