title: Antibody-mediated signaling through PD-1 costimulates T cells and enhances CD28-dependent proliferation.
abstract: Programmed death-1 (PD-1, CD279) is a molecule expressed on activated T, B and myeloid cells. The role of the interaction of PD-1 ligands (PD-L1 and PD-L2) with PD-1 receptor and the type of signals (costimulatory or inhibitory) that are delivered is a subject of intense debate. Our study has characterized two monoclonal antibodies (mAb) against murine PD-1, termed clone 1H10 and clone 4F10, that recognized different epitopes from that of anti-PD-1, clone J43. We showed that neither of them inhibited anti-CD3-mediated proliferation, but 1H10 mAb induced direct T cell proliferation in the absence of any other stimulus. Moreover, PD-1 engagement with 1H10 mAb costimulated anti-CD3-mediated proliferation and enhanced anti-CD3/CD28 proliferation on both CD4+ and CD8+ T cells in the low range of anti-CD3 concentrations. Anti-PD-1-mediated proliferation induced with 1H10 mAb was also observed in vivo on CD4+ and CD8+ T cells, when CFSE-labeled splenocytes were adoptively transferred to irradiated syngeneic and allogeneic recipients. Overall, our data indicate that PD-1 might not only deliver negative signals to T cells upon interaction through one of its ligands, PD-L1 as reported, but also could costimulate T cells, suggesting a dual potential functional activity of the extracellular domains of this receptor.
authors.affiliation: Unit of Transplantation Research, Arrixaca University Hospital, Murcia, Spain.
authors.forename: María-Luisa
authors.initials: ML
authors.lastname: del Rio
authors.forename: Giovanna
authors.initials: G
authors.lastname: Penuelas-Rivas
authors.forename: Raul
authors.initials: R
authors.lastname: Dominguez-Perles
authors.forename: Pablo
authors.initials: P
authors.lastname: Ramirez
authors.forename: Pascual
authors.initials: P
authors.lastname: Parrilla
authors.forename: Jose-Ignacio
authors.initials: JI
authors.lastname: Rodriguez-Barbosa
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000502:physiology*; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D018106:CD28 Antigens / Q000502:physiology*; D016466:CHO Cells; D049109:Cell Proliferation; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006825:Hybridomas; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018106:CD28 Antigens; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor