title: PD-L1/PD-1 signal deficiency promotes allogeneic immune responses and accelerates heart allograft rejection.
abstract: BACKGROUND
  PD-L1, a ligand for programmed death 1 (PD-1), delivers a negative costimulatory signal to T cells and plays a critical role in the regulation of peripheral tolerance.
  
  
  METHODS
  We used PD-L1(-/-) mice to evaluate the role of the PD-L1 signal on allogeneic immune responses in vivo and the underlying mechanisms. Heart transplantation was performed from PD-L1(-/-) donors or recipients in major histocompatibility complex fully mismatched mouse combinations. The immunologic function of allograft recipients was evaluated ex vivo by enzyme-linked immunospot, mixed lymphocytes reaction, cytotoxic T lymphocyte, and flow cytometry.
  
  
  RESULTS
  Our results demonstrated that PD-L1(-/-) T cells proliferated vigorously under alloantigen stimulation, and also that the antigen-presenting cells (APCs) from PD-L1(-/-) mice exhibited a stronger allostimulatory activity compared with that in wild-type mice. Heart allografts were rejected at an accelerated rate in both PD-L1(-/-) donors and recipients. This was associated with significantly augmented donor specific T-cell proliferation and antidonor cytotoxic T lymphocyte activities, and enhanced Th1- or Th2-type immune responses of heart allograft recipients.
  
  
  CONCLUSIONS
  Absence of PD-L1 input triggers a stimulatory signal to effector T cells and APCs, accelerating heart allograft rejection. Engagement of the PD-L1 signal on T cells or APCs may be necessary to induce transplant tolerance.
authors.affiliation: Division of Transplantation, Department of Surgery, University of Washington Medical Center, Seattle, WA 98195, USA.
authors.forename: Weigang
authors.initials: W
authors.lastname: Wang
authors.forename: Katie
authors.initials: K
authors.lastname: Carper
authors.forename: Frances
authors.initials: F
authors.lastname: Malone
authors.forename: Yvette
authors.initials: Y
authors.lastname: Latchman
authors.forename: James
authors.initials: J
authors.lastname: Perkins
authors.forename: Yaowen
authors.initials: Y
authors.lastname: Fu
authors.forename: Jorge
authors.initials: J
authors.lastname: Reyes
authors.forename: Wei
authors.initials: W
authors.lastname: Li
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics* / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology*; D060890:B7-H1 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008285:Major Histocompatibility Complex; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000172:deficiency* / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014184:Transplantation, Homologous / Q000276:immunology*
chemical_list: D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor