Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital, Harvard Medical School, Boston, MA.
Am J Transplant. 2010 May;10(5):1210-20. doi: 10.1111/j.1600-6143.2010.03089.x. Epub 2010 Mar 26.
CD8(+) memory T cells endanger allograft survival by causing acute and chronic rejection and prevent tolerance induction. We explored the role of CD27:CD70 T-cell costimulatory pathway in alloreactive CD8(+)/CD4(+) T-cell activation. CD27-deficient (CD27(-/-)) and wild-type (WT) B6 mice rejected BALB/c cardiac allografts at similar tempo, with or without depletion of CD4(+) or CD8(+) T cells, suggesting that CD27 is not essential during primary T-cell alloimmune responses. To dissect the role of CD27 in primed effector and memory alloreactive T cells, CD27(-/-) or WT mice were challenged with BALB/c hearts either 10 or 40 days after sensitization with donor-type skin grafts. Compared to WT controls, allograft survival was prolonged in day 40- but not day 10-sensitized CD27(-/-) recipients. Improved allograft survival was accompanied by diminished secondary responsiveness of memory CD8(+) T cells, which resulted from deficiency in memory formation rather than their lack of secondary expansion. Chronic allograft vasculopathy and fibrosis were diminished in CD27(-/-) recipients of class I- but not class II-mismatched hearts as compared to WT controls. These data establish a novel role for CD27 as an important costimulatory molecule for alloreactive CD8(+) memory T cells in acute and chronic allograft rejection.
CD8(+)记忆 T 细胞通过引起急性和慢性排斥反应来危害同种异体移植物的存活，并阻止诱导耐受。我们探讨了 CD27:CD70 T 细胞共刺激途径在同种反应性 CD8(+)/CD4(+)T 细胞激活中的作用。CD27 缺陷型（CD27(-/-)）和野生型（WT）B6 小鼠以相似的速度排斥 BALB/c 心脏同种异体移植物，无论是否耗尽 CD4(+)或 CD8(+)T 细胞，这表明 CD27 在原发性 T 细胞同种免疫反应中不是必需的。为了剖析 CD27 在已激活的效应器和记忆性同种反应性 T 细胞中的作用，CD27(-/-)或 WT 小鼠在致敏后 10 天或 40 天用 BALB/c 心脏进行挑战。与 WT 对照相比，在第 40 天而非第 10 天致敏的 CD27(-/-)受者中，同种异体移植物的存活时间延长。改善的同种异体移植物存活伴随着记忆性 CD8(+)T 细胞的次级反应性降低，这是由于记忆形成而不是缺乏次级扩增所致。与 WT 对照相比，CD27(-/-)受者的 I 类而非 II 类 mismatched 心脏的慢性同种异体移植物血管病和纤维化减轻。这些数据确立了 CD27 作为急性和慢性同种异体排斥反应中同种反应性 CD8(+)记忆 T 细胞的重要共刺激分子的新作用。
