Specificity requirements for selection and effector functions of CD25+4+ regulatory T cells in anti-myelin basic protein T cell receptor transgenic mice

CD25(+)4(+) regulatory T cells (T-reg) play an indispensable role in preventing autoimmunity. Little is known, however, about the antigen specificities required for their development and effector functions. Mice transgenic for an anti-myelin basic protein (MBP) T cell antigen receptor (TCR) spontaneously develop experimental autoimmune encephalomyelitis (EAE) when deficient for the RAG-1 gene (T/R-), whereas RAG-1-competent transgenic animals (T/R+) remain healthy, protected by CD4(+) T-reg-expressing endogenous TCRs. We have now investigated the role and specificity of CD25(+)4(+) T-reg in this system. The results show that T/R+ animals contain MBP-specific suppressive CD25(+)4(+) cells, whereas T/R- do not. Adoptive transfer of CD25(+)4(+) cells from nontransgenic or T/R+ donors into T/R- mice prevented the development of EAE. Surprisingly, transfer of nontransgenic CD25(+)4(+) cells purified from T/R+ donors conferred only a limited protection, possibly because of their restricted repertoire diversity that we demonstrate here. Absence of transgenic CD25(+)4(+) cells in animals deficient for endogenous TCRalpha chains and analyses of endogenous TCR gene expression in subsets of CD4(+) cells from T/R+ mice demonstrate that development of transgenic MBP-specific CD25(+)4(+) T-reg depends on the coexpression of endogenous TCRalpha chains. Taken together, these results indicate that specificity to MBP is required for effector functions but is not sufficient for thymic selection/commitment of CD25(+)4(+) T-reg preventing EAE.