Deletion of DOCK2, a regulator of the actin cytoskeleton in lymphocytes, suppresses cardiac allograft rejection
Deletion of DOCK2, a regulator of the actin cytoskeleton in lymphocytes, suppresses cardiac allograft rejection
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DOI：
10.1084/jem.20050911
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发表时间：
2005-10-17
影响因子：
15.3
通讯作者：
Fukui, Y
中科院分区：
文献类型：
--
作者：
Jiang, HS;Erickson, LM;Fukui, Y
同种异体移植物排斥反应是由同种异体反应性T细胞的移植物组织浸润诱导的，所述同种异体反应性T细胞主要在宿主的次级淋巴器官中被激活。DOCK 2通过调节肌动蛋白细胞骨架在淋巴细胞归巢和免疫突触形成中起关键作用，但其在体内免疫应答中的作用仍不清楚。我们在这里表明，DOCK 2缺陷使心脏移植物的长期生存，在一个完全不匹配的主要组织相容性复合体分子。在DOCK 2缺陷小鼠中，同种异体反应性和同种异体细胞毒性被显著抑制，即使在体内用同种异体抗原引发后也是如此，这导致效应分子如干扰素-γ、颗粒酶B和穿孔素的移植物内表达减少。这是介导的，至少部分是通过防止潜在的同种异体反应性T细胞招募到次级淋巴器官。此外，我们发现DOCK 2对CD 28介导的Rac活化至关重要，并且是同种异体反应性T细胞完全活化所必需的。虽然DOCK 2缺陷，同种异体反应性T细胞在体外激活外源性白细胞介素-2的存在下，这些T细胞，过继转移时，未能渗透到移植到RAG 1缺陷小鼠的同种异体移植物。因此，DOCK 2缺陷通过同时抑制多个关键过程来减弱同种异体移植物排斥。我们认为DOCK 2可能成为控制移植排斥反应的新分子靶点。
Allograft rejection is induced by graft tissue infiltration of alloreactive T cells that are activated mainly in secondary lymphoid organs of the host. DOCK2 plays a critical role in lymphocyte homing and immunological synapse formation by regulating the actin cytoskeleton, yet its role in the in vivo immune response remains unknown. We show here that DOCK2 deficiency enables long-term survival of cardiac allografts across a complete mismatch of the major histocompatibility complex molecules. In DOCK2-deficient mice, alloreactivity and allocytotoxicity were suppressed significantly even after in vivo priming with alloantigens, which resulted in reduced intragraft expression of effector molecules, such as interferon-gamma, granzyme B, and perforin. This is mediated, at least in part, by preventing potentially alloreactive T cells from recruiting into secondary lymphoid organs. In addition, we found that DOCK2 is critical for CD28-mediated Rac activation and is required for the full activation of alloreactive T cells. Although DOCK2-deficient, alloreactive T cells were activated in vitro in the presence of exogenous interleukin-2, these T cells, when transferred adoptively, failed to infiltrate into the allografts that were transplanted into RAG1-deficient mice. Thus, DOCK2 deficiency attenuates allograft rejection by simultaneously suppressing multiple and key processes. We propose that DOCK2 could be a novel molecular target for controlling transplant rejection.