Differential effects of B and T lymphocyte attenutator and programmed death-1 on acceptance of partially versus fully MHC-mismatched cardiac allografts
Differential effects of B and T lymphocyte attenutator and programmed death-1 on acceptance of partially versus fully MHC-mismatched cardiac allografts
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DOI：
10.4049/jimmunol.175.9.5774
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发表时间：
2005-11-01
影响因子：
4.4
通讯作者：
Hancock, WW
中科院分区：
文献类型：
--
作者：
Tao, R;Wang, LQ;Hancock, WW
尽管MHC完全不相合的小鼠心脏移植物被迅速排斥，但只有MHC I或II类等位基因不相合的同种异体移植物长期存活；MHC I或II类不相合的同种异体移植物长期存活的免疫学基础尚不清楚。我们研究了最近描述的两种抑制性受体，B和T淋巴细胞衰减器(BTLA)和程序性死亡-1(PD-1)，在使用基因缺陷受体的部分或完全MHC不相合的同种异体移植物存活中的作用，以及通过在野生型宿主中使用阻断单抗。部分MHC不相合的同种异体移植物表现出强烈的BTLA诱导，而不是PD-1mRNA，并在野生型受体中长期存活，而靶向BTLA或其配体，疱疹病毒进入媒介，而不是PD-1，促进了它们的快速排斥。相比之下，完全MHC不匹配的同种异体心脏移植在野生型受体中被强烈排斥，尽管BTLA和PD-1都被诱导了。在几种完全MHC不匹配的模型中靶向PD-1加速了排斥反应，而靶向BTLA意外地增强了同种反应性CD4和CD8T细胞诱导的PD-1，并延长了同种异体移植物的存活。使用同种异体树突状细胞和T细胞的体外研究表明，在低水平的T细胞激活时，主要诱导BTLA的表达，但随着T细胞激活程度的增加，PD-1的表达强烈上调。这些数据表明，BTLA和PD-1在体内具有明显的抑制作用，其中BTLA/疱疹病毒进入中介途径似乎在调节针对有限程度的同种异体错配的反应中占主导地位。
Although fully MHC-mismatched murine cardiac allografts are rapidly rejected, allografts mismatched at only MHC class I or class II alleles survive long term; the immunologic basis for the long-term survival of MHC class I- or II-mismatched allografts is unknown. We examined the roles of two recently described inhibitory receptors, B and T lymphocyte attenuator (BTLA) and programmed death-1 (PD-1), in the survival of partially or fully MHC-mismatched allografts using gene-deficient recipients as well as through use of blocking mAbs in wild-type hosts. Partially MHC-mismatched allografts showed strong induction of BTLA, but not PD-1 mRNA and survived long term in wild-type recipients, whereas targeting of BTLA or its ligand, herpesvirus entry mediator, but not PD-1, prompted their rapid rejection. By contrast, fully MHC-mismatched cardiac allografts were acutely rejected in wild-type recipients despite the induction of both BTLA and PD-1. Targeting of PD-1 in several fully MHC-mismatched models accelerated rejection, whereas targeting of BTLA unexpectedly enhanced PD-1 induction by alloreactive CD4 and CD8 T cells and prolonged allograft survival. In vitro studies using allogeneic dendritic cells and T cells showed that at low levels of T cell activation, BTLA expression was primarily induced, but that with increasing degrees of T cell activation, the expression of PD-1 was strongly up-regulated. These data suggest that BTLA and PD-1 exert distinct inhibitory actions in vivo, with the BTLA/herpesvirus entry mediator pathway appearing to dominate in regulating responses against a restricted degree of allogeneic mismatch.