Discoidin domain receptor 1 promotes T-cell migration in three-dimensional collagen by activatingthe RhoA/ROCK/MAPK/ERK signaling axis
Marc Boisvert1, Mohammed-Amine El Azreq1, Maleck Kadiri1, Nathalie Pagé1, Philippe A. Tessier1,2 and Fawzi Aoudjit1,2*
1Axe de Recherche sur les Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, QC, G1V 4G2, Canada;
2Département de Microbiologie-Immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 0A6, Canada
Effector T cell migration in extravascular tissues is an important step of the adaptive immune response against infections and cancer. However, the mechanisms involved in this process are still poorly understood. As the tumor microenvironment is rich in collagen, we addressed the role of a collagen receptor, the discoidin domain receptor 1 (DDR1). We showed that the vast majority of human Th1 and Th17 cells express DDR1 and silencing DDR1 or using the blocking recombinant receptor DDR1:Fc significantly reduced their motility and invasion capacity in three-dimensional (3D) collagen. In addition, DDR1 is also involved in the chemotaxis of human effector T-cells in 3D collagen. DDR1 promoted T-cell migration by activating the RhoA/ROCK and the MAPK/ERK signaling pathways concomitantly with the reduction of Rac1 activation. Finally, we showed that the CCL20-recruited Th17 cells to the mouse dorsal air pouch express DDR1, and that blockade of DDR1 significantly reduced their recruitment. Taken together, our results show that DDR1 is a key pathway in effector T cell migration through collagen and in perivascular tissues, suggesting a role for DDR1 in anti-cancer immunity.