title: The programmed death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo.
abstract: Programmed death-1 ligand 1 (PD-L1) is a coinhibitory molecule that negatively regulates multiple tolerance checkpoints. In the NOD mouse model, PD-L1 regulates the development of diabetes. PD-L1 has two binding partners, programmed death-1 and B7-1, but the significance of the PD-L1:B7-1 interaction in regulating self-reactive T cell responses is not yet clear. To investigate this issue in NOD mice, we have compared the effects of two anti-PD-L1 Abs that have different blocking activities. Anti-PD-L1 mAb 10F.2H11 sterically and functionally blocks only PD-L1:B7-1 interactions, whereas anti-PD-L1 mAb 10F.9G2 blocks both PD-L1:B7-1 and PD-L1:programmed death-1 interactions. Both Abs had potent, yet distinct effects in accelerating diabetes in NOD mice: the single-blocker 10F.2H11 mAb was more effective at precipitating diabetes in older (13-wk-old) than in younger (6- to 7-wk-old) mice, whereas the dual-blocker 10F.9G2 mAb rapidly induced diabetes in NOD mice of both ages. Similarly, 10F.2H11 accelerated diabetes in recipients of T cells from diabetic, but not prediabetic mice, whereas 10F.9G2 was effective in both settings. Both anti-PD-L1 mAbs precipitated diabetes in adoptive transfer models of CD4(+) and CD8(+) T cell-driven diabetes. Taken together, these data demonstrate that the PD-L1:B7-1 pathway inhibits potentially pathogenic self-reactive effector CD4(+) and CD8(+) T cell responses in vivo, and suggest that the immunoinhibitory functions of this pathway may be particularly important during the later phases of diabetogenesis.
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Paterson
authors.forename: Keturah E
authors.initials: KE
authors.lastname: Brown
authors.forename: Mary E
authors.initials: ME
authors.lastname: Keir
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Vanguri
authors.forename: Leonardo V
authors.initials: LV
authors.lastname: Riella
authors.forename: Anil
authors.initials: A
authors.lastname: Chandraker
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D015703:Antigens, CD / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D060890:B7-H1 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D005260:Female; D006131:Growth Inhibitors / Q000502:physiology*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D010455:Peptides / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D061026:Programmed Cell Death 1 Receptor; D011485:Protein Binding / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D006131:Growth Inhibitors; D008024:Ligands; D008562:Membrane Glycoproteins; C105992:PDCD1 protein, human; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor