Donor exosomes rather than passenger leukocytes initiate alloreactive T cell responses after transplantation
Donor exosomes rather than passenger leukocytes initiate alloreactive T cell responses after transplantation
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DOI：
10.1126/sciimmunol.aaf8759
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发表时间：
2016-07-01
影响因子：
24.8
通讯作者：
Benichou, Gilles
中科院分区：
文献类型：
--
作者：
Marino, Jose;Babiker-Mohamed, Mohamed H.;Benichou, Gilles
同种异体器官和组织移植对于各种患有终末期疾病的患者来说是一种挽救生命的方法。尽管目前的免疫抑制治疗可以预防早期急性排斥反应，但它与肾毒性以及感染和肿瘤风险增加有关。这强调需要依赖于操纵淋巴细胞对供体抗原的识别的选择性免疫疗法。过客白细胞理论指出，同种异体移植物排斥是由受体 T 细胞识别移植物白细胞上展示的供体主要组织相容性复合体 (MHC) 分子而引发的，并迁移到宿主的淋巴器官。我们使用成像流式细胞术在移植了同种异体皮肤、心脏或胰岛移植物的小鼠中重新审视了这一概念。我们在植皮小鼠的淋巴结和脾脏中没有观察到供体细胞，但我们发现大量受体细胞展示从供体微泡（外泌体）获得的同种异体 MHC 分子（异装）。心脏或胰岛移植后，我们观察到很少的供体白细胞（百万分之 100），但大量受体细胞与供体 MHC 异装（> 百万分之 90,000）。最后，我们证明纯化的同种异体外泌体在体外和体内诱导 T 细胞产生促炎同种免疫反应。总的来说，这些结果表明，同种异体移植后，与供体 MHC 异装的受体抗原呈递细胞（而不是过客白细胞）触发 T 细胞反应。
Transplantation of allogeneic organs and tissues represents a lifesaving procedure for a variety of patients affected with end-stage diseases. Although current immunosuppressive therapy prevents early acute rejection, it is associated with nephrotoxicity and increased risks for infection and neoplasia. This stresses the need for selective immune-based therapies relying on manipulation of lymphocyte recognition of donor antigens. The passenger leukocyte theory states that allograft rejection is initiated by recipient T cells recognizing donor major histocompatibility complex (MHC) molecules displayed on graft leukocytes migrating to the host's lymphoid organs. We revisited this concept in mice transplanted with allogeneic skin, heart, or islet grafts using imaging flow cytometry. We observed no donor cells in the lymph nodes and spleen of skin-grafted mice, but we found high numbers of recipient cells displaying allogeneic MHC molecules (cross-dressed) acquired from donor microvesicles (exosomes). After heart or islet transplantation, we observed few donor leukocytes (100 per million) but large numbers of recipient cells cross-dressed with donor MHC (>90,000 per million). Last, we showed that purified allogeneic exosomes induced proinflammatory alloimmune responses by T cells in vitro and in vivo. Collectively, these results suggest that recipient antigen-presenting cells cross-dressed with donor MHC rather than passenger leukocytes trigger T cell responses after allotransplantation.