Graca Luis, Le Moine Alain, Lin Chun-Yen, Fairchild Paul J, Cobbold Stephen P, Waldmann Herman
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom.
Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10122-6. doi: 10.1073/pnas.0400084101. Epub 2004 Jun 24.
To investigate the antigen specificity of regulatory T cells capable of preventing transplant rejection, we have developed two different strategies to achieve tolerance to fully mismatched skin grafts in euthymic mice. A combination of nondepleting Abs targeting CD4, CD8, and CD154 (CD40 ligand) induces dominant transplantation tolerance to fully mismatched skin allografts. Such tolerance is antigen-specific, mediated by regulatory T cells, and can be extended through linked suppression to naïve lymphocytes. The same protocol, when combined with allogeneic bone marrow, enables the development of mixed hematopoietic chimerism and deletional tolerance. Although we cannot exclude that some regulatory T cells may persist in chimeric mice, these cells are insufficient to mediate linked suppression. CD4(+)CD25(+) T cells, whether taken from naïve mice or from mice tolerized through either treatment protocol, were always able to prevent rejection of skin grafts by naïve CD4(+) T cells, and did so with no demonstrable specificity for the tolerizing donor antigens. Such data question whether CD4(+)CD25(+) regulatory T cells alone can account for the antigen specificity of dominant transplantation tolerance.
为了研究能够预防移植排斥反应的调节性T细胞的抗原特异性，我们开发了两种不同的策略，以在正常胸腺小鼠中实现对完全不匹配皮肤移植的耐受。靶向CD4、CD8和CD154（CD40配体）的非清除性抗体组合可诱导对完全不匹配皮肤同种异体移植物的显性移植耐受。这种耐受是抗原特异性的，由调节性T细胞介导，并且可以通过连锁抑制扩展到幼稚淋巴细胞。相同的方案与同种异体骨髓联合使用时，可促进混合造血嵌合体的形成和缺失性耐受。虽然我们不能排除某些调节性T细胞可能在嵌合小鼠中持续存在，但这些细胞不足以介导连锁抑制。CD4(+)CD25(+) T细胞，无论取自幼稚小鼠还是通过任一治疗方案耐受的小鼠，总是能够阻止幼稚CD4(+) T细胞对皮肤移植物的排斥，并且这样做对诱导耐受的供体抗原没有明显的特异性。这些数据质疑单独的CD4(+)CD25(+)调节性T细胞是否能够解释显性移植耐受的抗原特异性。
