Organ transplant rejection begins when a specific type of immune cell, known as a T cell, identifies foreign tissue and infiltrates the graft. It is not clear which molecular signals direct the T cells to begin migrating to the graft. Jeffrey Walch and colleagues used a mouse model of transplantation to show that T cells must recognize proteins expressed on the foreign tissue (antigens) in order to begin migrating to the graft. Similar to a search team presenting a piece of clothing to a blood hound, dendritic cells present antigens from the graft to the T cells. Once the T cell knows what it's looking for, it moves through the blood stream and through blood vessel walls in order to attack the foreign tissue. Here Walch and colleagues used time-lapse microscopy to monitor an antigen-targeted T cell (red) making stable contact (yellow) with a dendritic cell (green), triggering the migration process (the blood vessel is shown in blue). Videos of the migration are available here and here.
The migration of effector or memory T cells to the graft is a critical event in the rejection of transplanted organs. The prevailing view is that the key steps involved in T cell migration — integrin-mediated firm adhesion followed by transendothelial migration — are dependent on the activation of Gαi-coupled chemokine receptors on T cells. In contrast to this view, we demonstrated in vivo that cognate antigen was necessary for the firm adhesion and transendothelial migration of CD8+ effector T cells specific to graft antigens and that both steps occurred independent of Gαi signaling. Presentation of cognate antigen by either graft endothelial cells or bone marrow–derived APCs that extend into the capillary lumen was sufficient for T cell migration. The adhesion and transmigration of antigen-nonspecific (bystander) effector T cells, on the other hand, remained dependent on Gαi, but required the presence of antigen-specific effector T cells. These findings underscore the primary role of cognate antigen presented by either endothelial cells or bone marrow–derived APCs in the migration of T cells across endothelial barriers and have important implications for the prevention and treatment of graft rejection.
Jeffrey M. Walch, Qiang Zeng, Qi Li, Martin H. Oberbarnscheidt, Rosemary A. Hoffman, Amanda L. Williams, David M. Rothstein, Warren D. Shlomchik, Jiyun V. Kim, Geoffrey Camirand, Fadi G. Lakkis