The CD154-CD40 T cell costimulation pathway is required for host sensitization of CD8+ T cells by skin grafts via direct antigen presentation
The CD154-CD40 T cell costimulation pathway is required for host sensitization of CD8+ T cells by skin grafts via direct antigen presentation
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DOI：
10.4049/jimmunol.169.3.1270
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发表时间：
2002-08-01
影响因子：
4.4
通讯作者：
Kupiec-Weglinski, JW
中科院分区：
文献类型：
--
作者：
Zhai, Y;Shen, XD;Kupiec-Weglinski, JW
虽然CD154-CD40 T细胞共刺激通路已被证明在正常受者中介导同种异体免疫反应，但对其在致敏宿主中的作用知之甚少。在这项工作中，通过使用皮肤致敏的CD154和CD40缺陷小鼠的心脏移植排斥反应的新模型，我们重申了CD154-CD40信号在体内宿主对同种异体抗原增敏中的关键作用。首先，在我们的模型中，我们确定CD8(+)T细胞是执行加速性排斥反应的主要效应者。受者T细胞侧CD154-CD40信号中断(CD154缺失)，但APC侧(CD40缺失)受者CD154-CD40信号中断，移植物存活时间缩短(100天)。这表明宿主CD8(+)T细胞增敏中依赖于CD154的机制是通过直接的抗原提呈来实现的。然后，在对CD154缺陷和野生型受者的同种异体免疫反应的比较研究中，我们发现，尽管同种异体反应的B细胞反应被抑制，但同种异体反应的T细胞反应在CD8(+)T细胞中被选择性地下调，使CD4(+)T细胞基本不受影响。宿主同种异体反应性的这种独特的改变，不仅见于外周淋巴细胞，也见于同种异体移植物的浸润液，这可能是CD154-CD40信号中断在体内对同种异体抗原致敏并导致移植物长期存活的关键机制。
Although the CD154-CD40 T cell costimulation pathway has been shown to mediate alloimmune responses in normal recipients, little is known about its role in sensitized hosts. In this work, by using novel models of cardiac allograft rejection in Skin-sensitized CD154- and CD40-deficient mice, we reaffirm the key role of CD154-CD40 signaling in host sensitization to alloantigen in vivo. First, we identified CD8(+) T cells as principal effectors in executing accelerated rejection in our model. Disruption of CD154-CD40 signaling in recipients at the T cell side (CD154-deficient) but not at the APC side (CD40-defleient) abrogated accelerated (100 days) graft survival. This suggests that the CD154-dependent mechanism in host CD8(+) T cell sensitization operates via the direct Ag presentation. Then, in comparative studies of alloimmune responses in CD154-deficient and wild-type recipients, we showed that, although alloreactive B cell responses were inhibited, alloreactive T cell responses were down-regulated selectively in the CD8(+) T cell compartment, leaving CD4(+) T cells largely unaffected. This unique alteration in host alloreactivity, seen not only in peripheral lymphocytes but also in allograft infiltrate, may represent the key mechanism by which disruption of CD154-CD40 signaling presents sensitization to alloantigen in vivo and leads to long-term allograft survival.