Specificity requirements for selection and effector functions of CD25+4+ regulatory T cells in anti-myelin basic...

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.