title: Involvement of the programmed death-1/programmed death-1 ligand pathway in CD4+CD25+ regulatory T-cell activity to suppress alloimmune responses.
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.
authors.affiliation: Laboratory of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kitazawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujino
authors.forename: Quanxing
authors.initials: Q
authors.lastname: Wang
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kimura
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Masato
authors.initials: M
authors.lastname: Kubo
authors.forename: Ryo
authors.initials: R
authors.lastname: Abe
authors.forename: Xiao-Kang
authors.initials: XK
authors.lastname: Li
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000954:Antigens, Surface / Q000276:immunology / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000502:physiology*; D015551:Autoimmunity / Q000276:immunology* / Q000502:physiology; D051927:CD24 Antigen; D006084:Graft Rejection / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit; D007519:Isoantigens / Q000276:immunology; D008024:Ligands; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000502:physiology*; D016038:Skin Transplantation / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000502:physiology*; D023001:Transplantation Tolerance / Q000276:immunology* / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D051927:CD24 Antigen; D053645:Interleukin-2 Receptor alpha Subunit; D007519:Isoantigens; D008024:Ligands; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor