CD8 T-cell recognition of acquired alloantigen promotes acute allograft rejection
CD8 T-cell recognition of acquired alloantigen promotes acute allograft rejection
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DOI：
10.1073/pnas.1513533112
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发表时间：
2015-10-13
影响因子：
11.1
通讯作者：
Pettigrew, Gavin J.
中科院分区：
文献类型：
--
作者：
Harper, Simon J. F.;Ali, Jason M.;Pettigrew, Gavin J.
适应性 CD8 T 细胞免疫是细胞同种免疫反应的主要武器，但其发展需要帮助。这可以由“间接”识别同种异体抗原（作为自我限制性同种肽）的 CD4 T 细胞提供，但这一过程仍然无法解释，因为 CD4 和 CD8 T 细胞识别的目标表位在不同细胞（分别是受体和供体抗原呈递细胞 (APC)）上是“不相关的”。在这里，我们测试了这样的假设：受体树突状细胞（DC）（“半直接”途径）呈现完整和加工的 MHC I 类同种抗原，允许通过间接途径 CD4 T 细胞传递相关帮助，以产生破坏性的细胞毒性 CD8 T 细胞同种异体反应。我们发现，CD8 T 细胞介导的缺乏造血 APC 的小鼠同种异体心脏移植物的排斥反应需要宿主次级淋巴组织 (SLT)。 SLT 是必要的，因为在其中，受体树突状细胞可以从移植物实质细胞获得 MHC，同时将其作为完整蛋白呈递给同种异体反应性 CD8 T 细胞，并作为加工后的肽同种异体抗原以供间接途径 CD4 T 细胞识别。这能够为产生导致快速同种异体移植排斥的细胞毒性 CD8 T 细胞反应提供必要的帮助。在证明半直接途径与移植排斥的功能相关性时，我们的研究结果为一个长期存在的难题提供了解决方案，即为什么移植物实质细胞的 CD8 T 细胞同种异体识别需要 SLT，并提出了一种机制，通过该机制，间接途径 CD4 T 细胞有助于在移植后的较晚时间点产生效应细胞毒性 CD8 T 细胞同种异体反应。
Adaptive CD8 T-cell immunity is the principal arm of the cellular alloimmune response, but its development requires help. This can be provided by CD4 T cells that recognize alloantigen "indirectly," as self-restricted allopeptide, but this process remains unexplained, because the target epitopes for CD4 and CD8 T-cell recognition are "unlinked" on different cells (recipient and donor antigen presenting cells (APCs), respectively). Here, we test the hypothesis that the presentation of intact and processed MHC class I alloantigen by recipient dendritic cells (DCs) (the "semidirect" pathway) allows linked help to be delivered by indirect-pathway CD4 T cells for generating destructive cytotoxic CD8 T-cell alloresponses. We show that CD8 T-cell-mediated rejection of murine heart allografts that lack hematopoietic APCs requires host secondary lymphoid tissue (SLT). SLT is necessary because within it, recipient dendritic cells can acquire MHC from graft parenchymal cells and simultaneously present it as intact protein to alloreactive CD8 T cells and as processed peptide alloantigen for recognition by indirect-pathway CD4 T cells. This enables delivery of essential help for generating cytotoxic CD8 T-cell responses that cause rapid allograft rejection. In demonstrating the functional relevance of the semidirect pathway to transplant rejection, our findings provide a solution to a long-standing conundrum as to why SLT is required for CD8 T-cell allorecognition of graft parenchymal cells and suggest a mechanism by which indirect-pathway CD4 T cells provide help for generating effector cytotoxic CD8 T-cell alloresponses at late time points after transplantation.