We demonstrate that transfer of OVA-specific DO11 CD4+ T cells into mice that lack T and B cells and produce secreted OVA as an endogenous self-protein results in a severe systemic autoimmune reaction with skin inflammation, wasting, and death. The transferred DO11 T cells undergo massive expansion and produce IL-2 and IFN-γ abundantly. Transfer of DO11 cells into OVA-expressing animals in which T cells are absent but B cells are present, leads to mild disease with no death. In this situation, the DO11 cells undergo similar expansion but show poor Th1 differentiation. This regulatory effect of B cells correlates with profound TCR down-regulation. If T cells are present, the DO11 cells fail to expand independent of B cells. These results suggest that both endogenous T and B lymphocytes control T cell tolerance induction and pathogenicity, but at different stages of an anti-self response. Although endogenous T cells prevent expansion and maintain homeostasis, endogenous B cells limit subsequent effector responses of autoreactive CD4+ T cells.