One unresolved issue in immune tolerance is what prevents self-reactive T cells from activation. In this study, we used a transgenic mouse model of targeted functional inactivation of TGF-βR signaling in CD11c⁺ cells (CD11c^dnR mice) and showed a direct impact on the development of experimental autoimmune encephalomyelitis (EAE). We found that MOG_35–55 immunization of CD11c^dnR mice results in strong inflammation of CNS, high frequency of T cells in CNS, increased levels of T helper 1 (T_H1) and T_H17 cytokines in the periphery, and lack of remission from EAE. Once crossed with mice prone to autoimmunity, double-transgenic CD11c^dnRMog^TCR mice revealed a spontaneous EAE-like disease characterized by early infiltration of activated myelin-specific T cells into CNS, activation of microglial cells, inflammation of CNS, dysfunction of locomotion, and premature death. We constructed chimeric mice and demonstrated that inactivation of TGF-βR signaling in dendritic cells (DCs) results in augmented EAE-associated T cell responses. Our data provide direct evidence that TGF-β can control autoimmunity via actions on DCs.