Significance In spite of TNF involvement in the pathogenesis of multiple sclerosis (MS), systemic TNF neutralization in MS patients was not successful. One of the possible reasons is that TNF possesses both pathogenic and protective features that may be related to TNFR1 versus TNFR2 receptor engagement. This study uncovers one of such protective functions of TNF mediated by intrinsic TNFR2 signaling in T _reg cells. In mice bearing humanized TNF and TNFR2 genetic loci, TNFR2 ablation restricted to T _reg cells led to reduced capacity to control Th17 cell responses, exacerbated experimental autoimmune encephalomyelitis (EAE) development, and affected the maintenance of T _reg cells. These findings provide support for the emerging role of TNFR2 signaling in autoimmunity, as demonstrated here in mice with conditional inactivation of TNFR2.