Expression and function of discoidin domain receptor 1 in T cells

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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. Aim I: DDR1 expression and function in T cell subsets: To further explore the role of DDR1 in immune response, we will examine its expression and migratory function in human T cell subsets including Th1, Th2 and Th17 and Tc1, Tc2 and Tc17. Both ex-vivo and in vitro polarized T cell subsets will be characterized. Aim II: DDR1 in T cell survival and signaling: In addition of promoting cell movement, DDR1 can also favour T cell survival in 3D collagen. Thus, we will assess this possibility by determining the role of DDR1 in the regulation of T cell apoptosis in 3D collagen and in the regulation of pro- and anti-apoptotic Bcl-2 proteins. We will also examine the implication of MAPK, PI3 kinase/AKT and JAK/STAT pathways in DDR1-mediated T cell survival and in actomyosin contraction and we will define the DDR1-interacting proteins. Aim III: Role of DDR1 in protective immunity: To further explore the role of DDR1 in vivo and in the development of immune response, we will examine the role of DDR1 in anti-microbial immunity (mouse model of S. Pneumoniae infection) using the DDR1 KO mice and T cell transfer experiments in nude mice. Significance: These studies will bring new insights and understanding of the mechanisms involved in T cell migration in perivascular tissues and consequently in the mechanisms of host defense and protective immunity. Since cell migration is a process executed by all nucleated cells, we believe that our studies will have significant impact in understanding other processes such as morphogenesis and tissue regeneration.