Yamazaki M, Pearson T, Brehm M A, Miller D M, Mangada J A, Markees T G, Shultz L D, Mordes J P, Rossini A A, Greiner D L
Department of Medicine, Division of Diabetes, University of Massachusetts Medical School, Worcester, MA, USA.
Am J Transplant. 2007 Jul;7(7):1710-21. doi: 10.1111/j.1600-6143.2007.01839.x.
Regulatory T cells (Treg) are important in peripheral tolerance, but their role in establishing and maintaining hematopoietic mixed chimerism and generating central tolerance is unclear. We now show that costimulation blockade using a donor-specific transfusion and anti-CD154 antibody applied to mice given bone marrow and simultaneously transplanted with skin allografts leads to hematopoietic chimerism and permanent skin allograft survival. Chimeric mice bearing intact skin allografts fail to generate effector/memory T cells against allogeneic targets as shown by the absence of IFNgamma-producing CD44(high)CD8+ T cells and in vivo cytotoxicity. Depletion of Tregs by injection of anti-CD4 or anti-CD25 antibody prior to costimulation blockade prevents chimerism, shortens skin allograft survival and leads to generation of effector/memory cytotoxic T cells. Depletion of Tregs by injection of anti-CD4 or anti-CD25 antibody two months after transplantation leads to loss of skin allografts even though mice remain chimeric and exhibit little in vivo cytotoxicity. In contrast, chimerism is lost, but skin allografts survive following naïve T-cell injection. We conclude that hematopoietic chimerism and peripheral tolerance may be maintained by different mechanisms in mixed hematopoietic chimeras.
调节性T细胞（Treg）在外周耐受中起重要作用，但其在建立和维持造血混合嵌合体以及产生中枢耐受中的作用尚不清楚。我们现在表明，对接受骨髓移植并同时移植同种异体皮肤的小鼠，使用供体特异性输血和抗CD154抗体进行共刺激阻断，可导致造血嵌合体和同种异体皮肤移植永久存活。如缺乏产生IFNγ的CD44(高)CD8+ T细胞及体内细胞毒性所示，带有完整同种异体皮肤移植的嵌合小鼠无法产生针对同种异体靶标的效应/记忆T细胞。在共刺激阻断之前注射抗CD4或抗CD25抗体清除Treg可阻止嵌合体形成，缩短同种异体皮肤移植存活时间，并导致效应/记忆细胞毒性T细胞的产生。移植两个月后注射抗CD4或抗CD25抗体清除Treg会导致同种异体皮肤移植丧失，即使小鼠仍为嵌合体且体内细胞毒性很小。相反，嵌合体消失，但初次注射T细胞后同种异体皮肤移植仍存活。我们得出结论，在混合造血嵌合体中，造血嵌合体和外周耐受可能通过不同机制维持。
