Non-self recognition by monocytes initiates allograft rejection
Non-self recognition by monocytes initiates allograft rejection
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DOI：
10.1172/jci74370
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发表时间：
2014-08-01
影响因子：
15.9
通讯作者：
Lakkis, Fadi G.
中科院分区：
文献类型：
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作者：
Oberbarnscheidt, Martin H.;Zeng, Qiang;Lakkis, Fadi G.
激活T细胞的APC的成熟直接联系着先天免疫和获得性免疫，通常由微生物感染触发。同种异体移植物是无菌的，可产生强烈的T细胞反应；然而，在缺乏微生物来源的信号的情况下，移植物如何诱导APC成熟尚不清楚。一个被广泛接受的假设是移植物中的死亡细胞释放“危险的”分子，诱导APC成熟并启动适应性同种免疫反应。在这里，我们证明了与死亡细胞相关的危险信号不足以启动同种免疫，但需要先天免疫系统识别同种异体。在WT以及T细胞、B细胞和先天性淋巴细胞缺陷小鼠中，同种异体移植诱导单核细胞持续分化为表达IL-12的成熟DC，并刺激T细胞增殖和干扰素-γ的产生。相反，同一小鼠的同种异体移植诱导了短暂且不太明显的单核细胞分化为DC，DC既不表达IL-12，也不刺激干扰素-γ的产生。在一个模型中，T细胞识别限于移植物上的单一外来抗原，只有当同种异体信号也被宿主的先天免疫系统感知时，才会发生排斥反应。这些发现强调了单核细胞对同种异体异体的先天识别在启动移植排斥反应中的重要性。
Maturation of T cell-activating APCs directly links innate and adaptive immunity and is typically triggered by microbial infection. Transplantation of allografts, which are sterile, generates strong T cell responses; however, it is unclear how grafts induce APC maturation in the absence of microbial-derived signals. A widely accepted hypothesis is that dying cells in the graft release "danger" molecules that induce APC maturation and initiate the adaptive alloimmune response. Here, we demonstrated that danger signals associated with dying cells are not sufficient to initiate alloimmunity, but that recognition of allogeneic non-self by the innate immune system is required. In WT as well as in T cell-, B cell-, and innate lymphoid cell-deficient mice, allogeneic grafts elicited persistent differentiation of monocytes into mature DCs that expressed IL-12 and stimulated T cell proliferation and IFN-gamma production. In contrast, syngeneic grafts in the same mice elicited transient and less pronounced differentiation of monocytes into DCs, which neither expressed IL-12 nor stimulated IFN-gamma production. In a model in which T cell recognition is restricted to a single foreign antigen on the graft, rejection occurred only if the allogeneic non-self signal was also sensed by the host's innate immune system. These findings underscore the importance of innate recognition of allogeneic non-self by monocytes in initiating graft rejection.