Cognate antigen directs CD8+ T cell migration to vascularized transplants

Abstract

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 Gα i -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 Gα i 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 Gα i , 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.

Central memory CD8+ T lymphocytes mediate lung allograft acceptance

“…Our findings, with regard to trafficking requirements of CD8 + T cells to pulmonary allografts, further extend the notion that lungs differ immunologically from other transplanted organs. It has been demonstrated recently that antigen recognition regulates trafficking of effector CD8 + T cells into murine heart grafts (71). Consistent with these data, we now demonstrate that in vitrogenerated central memory CD8 + T lymphocytes infiltrate lung allografts to a significantly larger extent compared with anti-third party central memory CD8 + T cells.…”

Laminins affect T cell trafficking and allograft fate

“…This observed acute antigen specificity was unexpected. In allografts, DCs reach processes through the vascular bed, present antigen, and promote T cell transmigration (63). While this finding has not been confirmed in HEVs, it may contribute to the antigen specificity of differences in T cell trafficking.…”

Transplant rejection and paradigms lost

“…These T cell populations also differed in their requirements for chemokine receptor or TCR activation in infiltrating the transplant (Figure 1). Inactivation of the chemokine receptor-linked Gα i protein signaling pathway with pertussis toxin prevented migration of CD8 + T cells bearing the non-donor-reactive TCR complex, but not T cells bearing the donor-reactive TCR complex (8). Similar conclusions have emerged in an analysis of T cell migration in an autoimmune mouse model of type 1 diabetes (9, 10).…”

“…Donor antigen-initiated responses, but not chemokine receptor-initiated responses, were shown to be responsible for the migration and adhesion of CD8 + donor-reactive TCR T cells to the capillary lumina, which in turn led to transmigration of donorreactive effector T cells into the transplant. Previously, donor endothelial cells were believed to be solely responsible for presentation of antigen to T cells migrating into by pertussis toxin-treated donor-reactive memory T cells was only slightly delayed compared with controls (8).…”

“…Against this theoretical backdrop, and influenced by the surprisingly weak therapeutic effect of antibodies directed against chemokine receptors upon transplant survival (5-7), Walch et al tested the authenticity of the classical leukocyte migration paradigm in mouse cardiac and renal transplant models (8). In short, they confirmed an important role for the integrin VLA-4, but found that the paradigm did not hold true for the role of chemokines in directing the massive influx of recipient anti-donor T cells in the allograft response.…”