Epicutaneous immunization of T cell receptor (TCR) transgenic (Tg) mice whose CD4(+) T cells are specific for the Ac1-11 fragment of myelin basic protein (MBP) with Ac1-11 elicits T cells with dominant suppressor/regulatory activity that confers protection against Ac1-11-induced experimental autoimmune encephalomyelitis. We now report that such disease-resistant MBP TCR Tg mice also harbor a sizeable fraction of peripheral CD4(+) T cells lacking surface expression of the Tg TCR beta chain and expressing diverse, endogenously rearranged TCR beta chains. Ex vivo incubation at physiological temperature caused the loss of neo-beta-chain expression and reversion to the MBP alphabeta TCR(+) phenotype. The presence of recombination activating gene 1 and 2 proteins in CD4(+) T cells with revised TCRs was consistent with effective V(D)J recombination activity. The emergence of these cells did not depend on the thymic compartment. We conclude that in mice epicutaneously immunized with an autoantigen, peripheral specific T cells are susceptible to multiple mechanisms of tolerance.