Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) in which autoreactive T cells ignites downstream pathogenic cascades. The orphan nuclear receptor, NR4A2, is identified to be a selectively upregulated gene in peripheral blood T cells from relapsing-remitting MS patients. Furthermore, selective upregulation of NR4A2 is observed in peripheral blood T cells and CNS-infiltrating T cells upon immunization with myelin peptide in experimental autoimmune encephalomyelitis (EAE). Intriguingly, IL-17 -producing helper T cells exclusively express NR4A2, suggesting that NR4A2 expression represents a pathogenic T cells in autoimmunity. In addition, a NR4A2 blockade by RNA interference ameliorated EAE, implying the intrinsic roles of NR4A2 in MS/EAE, and could serve as a novel therapeutic target of the diseases.