Donor dendritic cell-derived exosomes promote allograft-targeting immune response
Donor dendritic cell-derived exosomes promote allograft-targeting immune response
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DOI：
10.1172/jci84577
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发表时间：
2016-08-01
影响因子：
15.9
通讯作者：
Morelli, Adrian E.
中科院分区：
文献类型：
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作者：
Liu, Quan;Rojas-Canales, Darling M.;Morelli, Adrian E.
针对移植的同种异体移植物的免疫应答是由免疫系统引起的最有效的反应之一。急性排斥反应归因于供体树突状细胞（DC），其迁移到受体淋巴组织并直接激活针对供体MHC分子的同种异体反应性T细胞。在这里，使用小鼠心脏移植模型，我们确定只有少量的供体DC到达淋巴组织，并研究了这一有限的供体DC群体如何有效地启动同种异体反应性T细胞反应，导致急性排斥反应。在我们的小鼠模型中，供体MHC分子向受体常规DC（cDC）的有效传递依赖于从移植物迁移到淋巴组织的供体DC的细胞外囊泡（EV）的转移。这些EV与外来体具有共同的特征，并且被内化或保持附着于受体cDC。获得外泌体的CDCs被激活并触发同种异体反应性T细胞的完全激活。小鼠心脏移植后受体cDC的耗竭显著降低了供体MHC分子向直接同种异体反应性T细胞的呈递，并延迟了移植物排斥反应。这些发现支持供体EV的转移在产生同种异体移植物靶向免疫反应中的关键作用，并表明中断这一过程有可能抑制对同种异体移植物的免疫反应。
The immune response against transplanted allografts is one of the most potent reactions mounted by the immune system. The acute rejection response has been attributed to donor dendritic cells (DCs), which migrate to recipient lymphoid tissues and directly activate alloreactive T cells against donor MHC molecules. Here, using a murine heart transplant model, we determined that only a small number of donor DCs reach lymphoid tissues and investigated how this limited population of donor DCs efficiently initiates the alloreactive T cell response that causes acute rejection. In our mouse model, efficient passage of donor MHC molecules to recipient conventional DCs (cDCs) was dependent on the transfer of extracellular vesicles (EVs) from donor DCs that migrated from the graft to lymphoid tissues. These EVs shared characteristics with exosomes and were internalized or remained attached to the recipient cDCs. Recipient cDCs that acquired exosomes became activated and triggered full activation of alloreactive T cells. Depletion of recipient cDCs after cardiac transplantation drastically decreased presentation of donor MHC molecules to directly alloreactive T cells and delayed graft rejection in mice. These findings support a key role for transfer of donor EVs in the generation of allograft-targeting immune responses and suggest that interrupting this process has potential to dampen the immune response to allografts.