Programmed cell death 1 (PD-1) and its ligand PD-L1 are required for allograft tolerance.
Programmed cell death-1 (PD-1, CD279) and its widely expressed, inducible ligand, PD-L1 (CD274), together dampen T cell activation, but whether they are essential for allograft tolerance is unknown. We show, using gene-deficient mice and blocking mAbs in wild-type mice, that costimulation blockade is ineffectual in PD-1(-/-) or PD-L1(-/-) allograft recipients, or in wild-type allograft recipients treated with anti-PD-1 or anti-PD-L1 mAb. Alloreactive PD-1(-/-) CD4 and CD8 T cells had enhanced proliferation and cytokine production compared to wild-type controls, and anergy could not be induced in PD-1-deficient CD4 T cells. We conclude that without inhibitory signals from PD-1 ligation, alloantigen-induced T cell proliferation and expansion cannot be regulated by costimulation blockade, and peripheral tolerance induction cannot occur.
Wang
Liqing
L
Department of Pathology and Laboratory Medicine, Joseph Stokes Jr Research Institute and Biesecker Pediatric Liver Center, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104-4318, USA.
Han
Rongxiang
R
Hancock
Wayne W
WW
D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018122:B7-1 Antigen / Q000378:metabolism / Q000502:physiology*; D060890:B7-H1 Antigen; D049109:Cell Proliferation; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000235:genetics / Q000276:immunology; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D007519:Isoantigens / Q000502:physiology; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010455:Peptides / Q000378:metabolism / Q000502:physiology*; D061026:Programmed Cell Death 1 Receptor; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D023001:Transplantation Tolerance / Q000235:genetics / Q000276:immunology*; D014184:Transplantation, Homologous
D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D007519:Isoantigens; D008024:Ligands; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor