Involvement of the programmed death-1/programmed death-1 ligand pathway in CD4+CD25+ regulatory T-cell activity to suppress alloimmune responses

Transplantation. 2007 Mar 27;83(6):774-82. doi: 10.1097/01.tp.0000256293.90270.e8.

Abstract

Background: Immune regulatory CD4+CD25+ T (regulatory T; Treg) cells play a vital role in the induction and maintenance of self-tolerance. They are essential for the homeostasis of T cells, the prevention of autoimmunity, and the induction of tolerance to allogeneic donor grafts. However, the underlying mechanism of their functions remains mostly elusive. Therefore, we investigated here a crucial role of Treg cells in their response to alloantigen via the programmed death (PD)-1/PD-1 ligand (PD-L1) pathway.

Methods: In vitro mixed lymphocyte reaction (MLR) assay, graft-versus-host disease (GvHD) and a skin transplantation model were used to evaluate the mechanisms of PD-1/PD-L1 pathway.

Results: Blockade of the PD-1/PD-L1 pathway using anti-PD-L1 monoclonal antibodies (mAb) is found to inhibit Treg cell's ability to suppress and restore CD4+CD25-T-cell proliferation in vitro. GvHD was lethal after adoptive transfer of allogeneic C57BL/6 (H-2K) spleen cells to NOD/SCID (H-2K) mice unless CD25+ T cells were also included. Strikingly, the suppression of GvHD by CD25+ cells was abrogated by anti-PD-L1 mAb administration. The abrogation of Treg-cell-mediated suppression could also be demonstrated in a Balb/c (H-2K) to B6/Rag-2KO (H-2K) skin-allograft model.

Conclusions: The blockade of the PD-1/PD-L1 pathway abrogates Treg-mediated immunoregulation, thus suggesting that the PD-1/PD-L1 pathway is required for Treg suppression of the alloreactive responses of CD4+CD25-T cells. This finding has important implications for clarifying the mechanisms of allograft rejection and GvHD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • Antigens, Surface / immunology
  • Antigens, Surface / physiology*
  • Apoptosis Regulatory Proteins / immunology
  • Apoptosis Regulatory Proteins / physiology*
  • Autoimmunity / immunology*
  • Autoimmunity / physiology
  • CD24 Antigen
  • Graft Rejection / immunology
  • Graft vs Host Disease / immunology
  • Interleukin-2 Receptor alpha Subunit
  • Isoantigens / immunology
  • Ligands
  • Lymphocyte Culture Test, Mixed
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Programmed Cell Death 1 Receptor
  • Signal Transduction / physiology*
  • Skin Transplantation / immunology
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / physiology*
  • Transplantation Tolerance / immunology*
  • Transplantation Tolerance / physiology

Substances

  • Antibodies, Monoclonal
  • Antigens, Surface
  • Apoptosis Regulatory Proteins
  • CD24 Antigen
  • Interleukin-2 Receptor alpha Subunit
  • Isoantigens
  • Ligands
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor