Abstract
Understanding the evolution of the direct and indirect pathways of allorecognition following tissue transplantation is essential in the design of tolerance-promoting protocols. On the basis that donor bone marrow-derived antigen-presenting cells are eliminated within days of transplantation, it has been argued that the indirect response represents the major threat to long-term transplant survival, and is consequently the key target for regulation. However, the detection of MHC transfer between cells, and particularly the capture of MHC:peptide complexes by dendritic cells (DCs), led us to propose a third, semidirect, pathway of MHC allorecognition. Persistence of this pathway would lead to sustained activation of direct-pathway T cells, arguably persisting for the life of the transplant. In this study, we focused on the contribution of acquired MHC-class I on recipient DCs during the life span of a skin graft. We observed that MHC-class I acquisition by recipient DCs occurs for at least 1 month following transplantation and may be the main source of alloantigen that drives CD8(+) cytotoxic T cell responses. In addition, acquired MHC-class I:peptide complexes stimulate T cell responses in vivo, further emphasizing the need to regulate both pathways to induce indefinite survival of the graft.