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.
Highlights
The major obstacle to transplantation success is the recognition by the recipient immune system of donor major histocompatibility complex (MHC molecules) [1,2]
Results mOVA-expressing skin allografts are rejected in the absence of CD8a+ and CD103+ dendritic cell (DC)
Injection of OVA-specific CD8+ T cells, isolated from OT-1 T cell receptor (TCR)–transgenic mice, into these transplanted B6 mice indicated the presence of OVA antigen in both skin-draining lymph node (sdLN) and spleen following skin transplantation [15]
Summary
The major obstacle to transplantation success is the recognition by the recipient immune system of donor major histocompatibility complex (MHC molecules) [1,2]. Since we proposed the existence of the third pathway of allorecognition, based on the evidence that intact MHC-class I molecules can be transferred between DC subsets and between DCs and endothelial as well as epithelial cells, this assumption has been challenged [5,6,7,8]. The discovery of this new pathway of allorecognition suggests that the direct pathway could last for the life of the transplant and pose another challenge for the induction of long-term transplant survival [6]
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