Cross-Dressing by Donor Dendritic Cells after Allogeneic Bone Marrow Transplantation Contributes to Formation of the Immunological Synapse and Maximizes Responses to Indirectly Presented Antigen
Cross-Dressing by Donor Dendritic Cells after Allogeneic Bone Marrow Transplantation Contributes to Formation of the Immunological Synapse and Maximizes Responses to Indirectly Presented Antigen
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DOI：
10.4049/jimmunol.1302490
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发表时间：
2014-06-01
影响因子：
4.4
通讯作者：
Hill, Geoffrey R.
中科院分区：
文献类型：
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作者：
Markey, Kate A.;Koyama, Motoko;Hill, Geoffrey R.
受者同种异体抗原对初始供者T细胞的刺激是骨髓移植（BMT）后移植物抗宿主病（GVHD）发病机制的核心。使用移植的小鼠模型，我们已经观察到，供体细胞在BMT后变得“cross-dressed”在非常高水平的受体造血细胞衍生的MHC I类和II类分子中。受体型MHC在骨髓移植后清髓性条件下短暂存在于供体树突状细胞（DC）上，但在非清髓性条件下持续存在，其中受体造血细胞保持大量。尽管供体DC表面上存在高水平的供体来源的同种异体抗原，但供体T细胞增殖应答仅响应于通过间接途径呈递的经加工的受体同种异体抗原而产生，而不响应于交叉修饰的MHC。在对MHC II类-肽组合具有特异性的初始TCR转基因T细胞存在的情况下，将外源肽添加到交叉修饰的MHC中的测定证实，交叉修饰的APC不能单独诱导T细胞增殖。尽管不能诱导T细胞增殖，但供体DC的交叉修饰有助于DC和CD 4 T细胞之间的免疫突触的产生，并且这是经典的间接呈递同种异体抗原诱导的最大应答所必需的。我们的结论是，由供体DC的cross-dressing的过程中作为一个有效的替代途径，用于收购受体同种异体抗原，一旦收购，这种cross-dressed的MHC可以协助免疫突触的形成之前，通过并行间接Ag呈递诱导完整的T细胞增殖反应。
The stimulation of naive donor T cells by recipient alloantigen is central to the pathogenesis of graft-versus-host disease after bone marrow transplantation (BMT). Using mouse models of transplantation, we have observed that donor cells become "cross-dressed" in very high levels of recipient hematopoietic cell-derived MHC class I and II molecules following BMT. Recipient-type MHC is transiently present on donor dendritic cells (DCs) after BMT in the setting of myeloablative conditioning but is persistent after nonmyeloablative conditioning, in which recipient hematopoietic cells remain in high numbers. Despite the high level of recipientderived alloantigen present on the surface of donor DCs, donor T cell proliferative responses are generated only in response to processed recipient alloantigen presented via the indirect pathway and not in response to cross-dressed MHC. Assays in which exogenous peptide is added to cross-dressed MHC in the presence of naive TCR transgenic T cells specific to the MHC class II-peptide combination confirm that cross-dressed APC cannot induce T cell proliferation in isolation. Despite failure to induce T cell proliferation, cross-dressing by donor DCs contributes to generation of the immunological synapse between DCs and CD4 T cells, and this is required for maximal responses induced by classical indirectly presented alloantigen. We conclude that the process of cross-dressing by donor DCs serves as an efficient alternative pathway for the acquisition of recipient alloantigen and that once acquired, this cross-dressed MHC can assist in immune synapse formation prior to the induction of full T cell proliferative responses by concurrent indirect Ag presentation.