Hori Shohei, Haury Matthias, Coutinho António, Demengeot Jocelyne
Instituto Gulbenkian de Ciência, Apartado 14, 2781-901 Oeiras, Portugal.
Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8213-8. doi: 10.1073/pnas.122224799. Epub 2002 May 28.
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.
CD25(+)4(+)调节性T细胞（T(reg)）在预防自身免疫中发挥着不可或缺的作用。然而，对于其发育和效应功能所需的抗原特异性却知之甚少。当缺乏RAG-1基因（T/R(-)）时，转染抗髓鞘碱性蛋白（MBP）T细胞抗原受体（TCR）的小鼠会自发发生实验性自身免疫性脑脊髓炎（EAE），而具有RAG-1功能的转基因动物（T/R(+)）则保持健康，受到表达内源性TCR的CD4(+) T(reg)的保护。我们现在研究了该系统中CD25(+)4(+) T(reg)的作用和特异性。结果表明，T/R(+)动物含有MBP特异性抑制性CD25(+)4(+)细胞，而T/R(-)动物则没有。将来自非转基因或T/R(+)供体的CD25(+)4(+)细胞过继转移到T/R(-)小鼠中可预防EAE的发生。令人惊讶的是，从T/R(+)供体中纯化的非转基因CD25(+)4(+)细胞的转移仅提供了有限的保护，这可能是由于我们在此证明的其有限的库多样性。内源性TCRα链缺陷动物中缺乏转基因CD25(+)4(+)细胞以及对T/R(+)小鼠CD4(+)细胞亚群中内源性TCR基因表达的分析表明，转基因MBP特异性CD25(+)4(+) T(reg)的发育依赖于内源性TCRα链的共表达。综上所述，这些结果表明，对MBP的特异性是效应功能所必需的，但不足以进行胸腺选择/承诺CD25(+)4(+) T(reg)以预防EAE。
