Comprehensive analysis of role of dendritic cells and target cells in graft-versus-host disease and graft-versus-leukemia

供体和宿主之间的T细胞和树突状细胞（DC）的相互作用对于启动同种异体T细胞应答是至关重要的，例如实体器官和造血干细胞（HSC）的同种异体移植中的移植物排斥和移植物抗宿主病（GVHD）。FTY 720是一种新型的免疫抑制剂，由于T细胞被隔离到LN中，它改善了实体器官和骨髓移植（BMT）后的结果。我们测试的假设，供体T细胞在LN的隔离FTY 720将增强其与宿主APC的相互作用，从而导致更大程度的活化诱导的同种异体反应性T细胞的凋亡，从而导致GVHD的减少。短期应用FTY 720可提高异基因骨髓移植后受体的存活率。FTY 720处理促进了供体T细胞库的快速收缩，这与供体T细胞的凋亡程度增加有关。供体T细胞对宿主同种异体抗原的反应性降低， ...更多信息 d和过继转移从FTY 720处理的异基因BMT受体的LN分离的供体T细胞诱导次级受体的GVHD比从对照转移的严重性低。半胱天冬酶依赖性细胞凋亡参与了这一机制，因为当给予泛半胱天冬酶抑制剂时，FTY 720诱导的保护被废除。因此，这些发现证明了FTY 720调节同种异体T细胞应答的新机制的存在：即通过诱导LNs中同种异体反应性T细胞的活化诱导的凋亡。我们接下来使用仅在造血细胞上表达同种异体抗原的嵌合小鼠测试了宿主非造血细胞上的MHC和同种异体抗原表达在同种异体BMT后对移植物抗白血病（GVL）效应的作用。在非造血细胞上的同种异体抗原表达驱使供体T细胞进入活化诱导的细胞凋亡，并导致细胞毒性效应子功能失调，导致GVL活性降低。当非造血细胞缺乏MHC I类分子的表达时，在非造血细胞上缺乏同种异体抗原表达的嵌合小鼠中观察到的上级GVL活性被废除。结果表明，最大的GVL效应需要在非造血细胞上不存在同种异体抗原的情况下在APC上表达MHC分子。这些结果揭示了以前未被认识的意义上的MHC和同种异体抗原表达的非造血细胞的GVL效应，并提供了一个重要的框架，以了解GVL的病理生理GVL从GVHD的分离。DC可分为两个主要亚群;常规DC（cDC）和浆细胞样DC（pDC）。cDC可以引发初始T细胞，而pDC在器官移植中可以是致耐受性的。我们通过将表达MHC的pDC分别加入到对CD 4和CD 8-deoendent GVHD有抵抗力的MHC II类和2-微球蛋白缺陷小鼠中，测试了pDC是否可以在同种异体HSC移植的小鼠模型中引发同种异体T细胞。单独的pDC是足够的pDC，其不依赖于toll样受体信号传导。因此，pDC可以在发炎环境中引发同种异体T细胞，这些结果为开发旨在灭活DC以预防GVHD的策略提供了重要信息。少

Interactions of T cells and dendritic cells (DCs) between donors and hosts are critical to initiate allogeneic T cell responses, such as graft rejection and graft-versus-host disease (GVHD) in allogeneic transplantation of solid organs and hematopoietic stem cells (HSCs). FTY720 is a novel immunosuppressant that improves the outcomes after solid organ and bone marrow transplantation(BMT)due to the sequestration of T cells into LNs. We tested the hypothesis that the sequestration of donor T cells in LNs by FTY720 would enhance their interaction with host APCs, thus causing a greater degree of activation-induced apoptosis of alloreactive T cells, and thereby resulting in a reduction of GVHD. The short-term administration of FTY720 improved the recipient survival after allogeneic BMT. FTY720-treatment facilitated a rapid contraction of the donor T cell pool in association with an increased degree of apoptosis of donor T cells. The donor T cell reactivity to host alloantigens was diminishe … More d in host's LNs and adoptive transfer of donor T cells isolated from LNs of FTY720-treated recipients of allogeneic BMT induced less severe GVHD in secondary recipients than the transfer from controls. Caspase-dependent apoptosis was involved in this mechanism because FTY720-induced protection was abrogated when pan-caspase inhibitor was administered. These findings thus demonstrate the presence of a novel mechanism by which FTY720 modulates the allogeneic T cell responses: namely, by the induction of activation-induced apoptosis of alloreactive T cells in LNs.We next tested the role of MHC and alloantigen expression on host non-hematopoietic cells on graft-versus-leukemia (GVL) effects after allogeneic BMT using chimeric mice expressing alloantigens on hematopoietic cells 'alone. Alloantigen expression on non-hematopoietic cells drives donor T cells into activation-induced apoptosis and leads to dysfunctional cytotoxic effector function, resulting in a reduction of GVL activity. The superior GVL activity observed in chimeric mice that lacked alloantigen expression on non-hematopoietic cells was abrogated when non-hematopoietic cells lack expression of MHC class I molecules. The results demonstrate that maximum GVL effects require expression of MHC molecules on APCs in the absence of alloantigens on non-hematopoietic cells. These results unveiled the previously unrecognized significance of MHC and alloantigen expression on non-hematopoietic cells in GVL effects and provide an important framework to understand pathophysiology of GVL for the separation of GVL from GVHD. DCs can be divided into two main subpopulations; conventional DCs (cDCs) and plasmacytoid DCs(pDCs). cDCs can prime naive T cells, whereas pDCs can be tolerogenic in organ transplantation. We tested whether pDCs could prime allogeneic T cells in mouse models of allogeneic HSC transplantation by an add-back study of MHC-expressing pDCs into MHC class II and 2-micmglobulin deficient mice that were resistant to CD4 and CD8-deoendent GVHD, respectively. pDCs alone were sufficient of pDCs that was independent on toll-like receptor signaling. Thus pDCs can prime allogeneic T cells in an inflamed environment and these results provide important information for developing strategies aimed at inactivating DCs to prevent GVHD. Less