Expression and function of discoidin domain receptor 1 in T cells

T细胞中盘状蛋白结构域受体1的表达和功能

• 批准号: RGPIN-2017-06116
• 负责人: Aoudjit, Fawzi
• 金额: $ 2.48万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=629589
• 关键词: Expression; function; discoidin; domain; receptor

For an effective immune response and to reach target tissues, activated/effector T cells must overcome the barriers of the blood vessels as well as the extracellular matrix (ECM) of the basement membrane and of the interstitial stroma, which is constituted mainly of collagen. The use of three-dimensional (3D) models such as collagen gels revealed that activated T cells use the amoeboid movement to migrate in collagen independently from strong adhesive forces and integrins. In this regard, we and others previously reported that the discoidin domain receptor 1 (DDR1), a tyrosine kinase receptor, which binds collagens, is induced during T cell activation and participates in the migration of activated human T cells in 3D collagen. We recently demonstrated that the vast majority of human Th17 cells express DDR1 but not DDR2 and that silencing DDR1 or using the blocking recombinant receptor (DDR1:Fc) significantly reduced their migration in 3D collagen. DDR1 promoted amoeboid movement of Th17 cells by activating the RhoA/ROCK/MAPK/ERK signaling axis. Finally, we showed that DDR1 is important for the recruitment of Th17 cells in vivo (mouse air pouch model). The mechanisms of effector T cell migration in perivascular tissues are still poorly understood. Thus, based on our studies, we propose that DDR1 can be a major receptor in T cell migration and in the development of immune response.

为了有效的免疫应答和到达靶组织，活化/效应T细胞必须克服血管的屏障以及基底膜和间质基质的细胞外基质（ECM），其主要由胶原蛋白构成。使用三维（3D）模型，如胶原蛋白凝胶显示，活化的T细胞使用变形运动在胶原蛋白中迁移，独立于强粘附力和整合素。在这方面，我们和其他人以前报道，盘状结构域受体1（DDR 1），酪氨酸激酶受体，结合胶原蛋白，诱导T细胞活化过程中，并参与在三维胶原蛋白中的活化的人T细胞的迁移。我们最近证明，绝大多数人Th 17细胞表达DDR 1但不表达DDR2，并且沉默DDR 1或使用阻断重组受体（DDR 1：Fc）显著降低了它们在3D胶原中的迁移。DDR 1通过激活RhoA/ROCK/MAPK/ERK信号轴促进Th 17细胞的变形运动。最后，我们表明DDR 1对于体内Th 17细胞的募集是重要的（小鼠气囊模型）。效应T细胞在血管周围组织中迁移的机制仍然知之甚少。因此，基于我们的研究，我们提出DDR 1可以是T细胞迁移和免疫应答发展中的主要受体。