Hepatocyte Growth Factor Receptor c-Met Instructs T Cell Cardiotropism and Promotes T Cell Migration to the Heart via Autocrine Chemokine Release.
Hepatocyte Growth Factor Receptor c-Met Instructs T Cell Cardiotropism and Promotes T Cell Migration to the Heart via Autocrine Chemokine Release.
复制标题
肝细胞生长因子受体C-MET指示T细胞心形成，并通过自分泌趋化因子释放促进T细胞迁移到心脏。
DOI：
10.1016/j.immuni.2015.05.014
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发表时间：
2015-06-16
期刊：
影响因子：
32.4
通讯作者：
Marelli-Berg FM
中科院分区：
文献类型：
--
作者：
Komarowska I;Coe D;Wang G;Haas R;Mauro C;Kishore M;Cooper D;Nadkarni S;Fu H;Steinbruchel DA;Pitzalis C;Anderson G;Bucy P;Lombardi G;Breckenridge R;Marelli-Berg FM
免疫原性T细胞介导的免疫依赖于抗原致敏的淋巴细胞有效定位于富含抗原的非淋巴组织，这是由记忆T细胞获得的一组独特的“归巢”受体的表达促进的。我们报告了在淋巴结中引发期间，心脏产生的肝细胞生长因子（HGF）与肝细胞生长因子（HGF）受体c-Met的接合指示T细胞向心性，这与专门的归巢“签名”（c-Met+ CCR 4 + CXCR 3+）相关。c-Met信号通过诱导自分泌CCR 5配体释放，促进T细胞通过趋化因子受体CCR 5募集到心脏。c-Met触发足以支持亲心性T细胞再循环，而CCR 4和CXCR 3在心脏炎症期间持续募集。在T细胞引发期间c-Met的瞬时药理学阻断导致心脏而非皮肤移植物的存活增强，这与同种异体反应性T细胞在心脏移植物中的定位受损相关。这些发现表明c-Met是器官选择性免疫抑制疗法开发的靶点。HGF诱导的c-Met信号在激活过程中诱导向心记忆T细胞（c-Met+ CCR 4 + CXCR 3+）通过诱导自分泌趋化因子环，c-Met还促进T细胞募集。同种异体移植排斥反应了解印记组织的信号-特异性免疫细胞归巢可能导致靶向炎症性疾病的新方法。Marelli-Berg及其同事报告说，肝细胞生长因子与其受体c-Met结合指示T细胞归巢心脏，c-Met的药理学阻断可预防心脏中T细胞介导的炎症，但不能预防皮肤。
Effector-T-cell-mediated immunity depends on the efficient localization of antigen-primed lymphocytes to antigen-rich non-lymphoid tissue, which is facilitated by the expression of a unique set of “homing” receptors acquired by memory T cells. We report that engagement of the hepatocyte growth factor (HGF) receptor c-Met by heart-produced HGF during priming in the lymph nodes instructs T cell cardiotropism, which was associated with a specialized homing “signature” (c-Met+CCR4+CXCR3+). c-Met signals facilitated T cell recruitment to the heart via the chemokine receptor CCR5 by inducing autocrine CCR5 ligand release. c-Met triggering was sufficient to support cardiotropic T cell recirculation, while CCR4 and CXCR3 sustained recruitment during heart inflammation. Transient pharmacological blockade of c-Met during T cell priming led to enhanced survival of heart, but not skin, allografts associated with impaired localization of alloreactive T cells to heart grafts. These findings suggest c-Met as a target for development of organ-selective immunosuppressive therapies. HGF-induced c-Met signals during activation induce cardiotropic memory T cells Cardiotropic T cells express a specific molecular signature (c-Met+CCR4+CXCR3+) By inducing an autocrine chemokine loop, c-Met also promotes T cell recruitment Blockade of the HGF-c-Met axis prevents heart, but not skin, allograft rejection Understanding the signals that imprint tissue-specific immune cell homing might result in novel approaches to target inflammatory disease. Marelli-Berg and colleagues report that hepatocyte growth factor binding to its receptor c-Met instructs T cell homing to the heart, and pharmacological blockade of c-Met prevents T-cell-mediated inflammation in the heart but not the skin.