Continuous Acquisition of MHC:Peptide Complexes by Recipient Cells Contributes to the Generation of Anti-Graft CD8+ T Cell Immunity

Am J Transplant. 2017 Jan;17(1):60-68. doi: 10.1111/ajt.13996. Epub 2016 Sep 14.

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.

Keywords: basic (laboratory) research/science; cytotoxicity; histocompatibility; immune regulation; immunobiology; immunosuppression/immune modulation; innate immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allografts
  • Animals
  • Antigen Presentation / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • Dendritic Cells / immunology*
  • Graft Rejection / immunology*
  • Graft Rejection / pathology
  • Immune Tolerance / immunology
  • Immunity, Cellular / immunology*
  • Isoantigens / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Peptide Fragments / immunology*
  • Skin Transplantation / adverse effects*
  • Tissue Donors
  • Transplant Recipients

Substances

  • Isoantigens
  • Peptide Fragments