趋化因子调控整合素α4β7配体识别特异性的机制及其功能研究

The immune surveillance and host defense depend on the precisely regulated trafficking of lymphocytes. Integrin expression on the lymphocyte coupled with the expression of integrin ligands on different tissues is important for determining the tissue specificity of lymphocyte homing. Integrin α4β7 mediates lymphocyte homing to gut-associated lymphoid tissues through its interaction with MAdCAM-1, which is specifically expressed in gut-associated lymphoid tissues; whereas it also binds VCAM-1 which is widely expressed in other tissues. The ability of α4β7 to bind multiple ligands interferes with the precise lymphocytes trafficking to the tissues expressing either MAdCAM-1 or VCAM-1. To maintain the tissue-specific lymphocyte homing, integrin α4β7 must distinguish one ligand from the other. Our preliminary study has shown that integrin α4β7 can be activated by distinct chemokines in a ligand-specific manner through differential signaling pathways. Herein, we will further study the molecular mechanism of integrin ligand specificity regulated by different chemokine signaling pathways and the biological function of lymphocyte tissue-specific homing triggered by different chemokines at animal level. This study will provide a novel mechanism for lymphocyte traffic control through the unique ligand-specific regulation of integrin adhesion by different chemokines, and facilitate the development of new therapeutics for integrin α4β7 related disease.

淋巴细胞的组织特异性归巢是机体免疫与宿主防御的关键环节，其组织特异性是由表达在淋巴细胞表面的整合素与表达在不同组织中的配体蛋白相互作用而决定的。整合素α4β7通过与配体MAdCAM-1（肠道组织特异性表达）结合从而介导淋巴细胞特异性向肠道组织迁移；另一方面，α4β7还可以识别配体VCAM-1（其它多种组织均有表达）。因此，整合素α4β7必须区分这两种配体蛋白才能确保淋巴细胞选择性迁移至特定的组织。在本项目的研究中，目前已发现不同趋化因子通过活化不同的胞内信号通路，进而调控整合素α4β7识别不同的配体。我们将进一步研究不同趋化因子调控整合素配体识别特异性的分子机制，同时在动物水平研究不同趋化因子通过该机制确保淋巴细胞组织特异性迁移的生物学意义。该研究将揭示一种趋化因子通过改变整合素配体识别特异性而精确调控淋巴细胞组织特异性归巢的全新机制，并为整合素α4β7相关疾病的治疗以及药物筛选。

淋巴细胞的组织特异性归巢是机体免疫与宿主防御的关键环节，其组织特异性是由表达在淋巴细胞表面的整合素与表达在不同组织中的配体蛋白相互作用而决定的。整合素a4b7通过与配体MAdCAM-1（肠道组织特异性表达）结合从而介导淋巴细胞特异性向肠道组织迁移；另一方面，a4b7还可以识别配体VCAM-1（其它多种组织均有表达）。因此，整合素a4b7必须区分这两种配体蛋白才能确保淋巴细胞选择性迁移至特定的组织。在本项目的研究中，目前已发现不同趋化因子通过活化不同的胞内信号通路，进而调控整合素a4b7识别不同的配体。我们将进一步研究不同趋化因子调控整合素配体识别特异性的分子机制，同时在动物水平研究不同趋化因子通过该机制确保淋巴细胞组织特异性迁移的生物学意义。该研究将揭示一种趋化因子通过改变整合素配体识别特异性而精确调控淋巴细胞组织特异性归巢的全新机制，并为整合素a4b7相关疾病的治疗以及药物筛选提供理论基础和指导。