The molecular-mimicry theory proposes that immune crossreactivity between microbial and self-antigen is the initiating event in the activation of autoaggressive immune responses leading to autoimmune disease. In support of this possibility, it is now accepted that T cell recognition of antigen is highly degenerate. However, it is to be expected that the immune system would have evolved mechanisms to counter such a potential danger. We studied the influence of CD4(+)CD25(+) regulatory T cells (Treg) on the ability of suboptimal T cell receptor ligands to provoke autoimmunity. By using CD4(+) T cell-driven experimental autoimmune encephalomyelitis as a model, it was found that depletion of CD4(+)CD25(+)Foxp3(+) Treg allowed pathology to develop in response to suboptimal T cell stimulation. These data demonstrate the importance of Treg in raising the threshold of triggering of autoreactive T cell responses, thus limiting the risk of autoimmune disease due to molecular mimicry.