title: Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.
abstract: PD-1 is an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells. Mice deficient in PD-1 exhibit a breakdown of peripheral tolerance and demonstrate multiple autoimmune features. We report here that the ligand of PD-1 (PD-L1) is a member of the B7 gene family. Engagement of PD-1 by PD-L1 leads to the inhibition of T cell receptor-mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-L1 is expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon gamma, and activated human and murine dendritic cells. In addition, PD-L1 is expressed in nonlymphoid tissues such as heart and lung. The relative levels of inhibitory PD-L1 and costimulatory B7-1/B7-2 signals on antigen-presenting cells may determine the extent of T cell activation and consequently the threshold between tolerance and autoimmunity. PD-L1 expression on nonlymphoid tissues and its potential interaction with PD-1 may subsequently determine the extent of immune responses at sites of inflammation.
authors.affiliation: Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: A J
authors.initials: AJ
authors.lastname: Long
authors.forename: Y
authors.initials: Y
authors.lastname: Iwai
authors.forename: K
authors.initials: K
authors.lastname: Bourque
authors.forename: T
authors.initials: T
authors.lastname: Chernova
authors.forename: H
authors.initials: H
authors.lastname: Nishimura
authors.forename: L J
authors.initials: LJ
authors.lastname: Fitz
authors.forename: N
authors.initials: N
authors.lastname: Malenkovich
authors.forename: T
authors.initials: T
authors.lastname: Okazaki
authors.forename: M C
authors.initials: MC
authors.lastname: Byrne
authors.forename: H F
authors.initials: HF
authors.lastname: Horton
authors.forename: L
authors.initials: L
authors.lastname: Fouser
authors.forename: L
authors.initials: L
authors.lastname: Carter
authors.forename: V
authors.initials: V
authors.lastname: Ling
authors.forename: M R
authors.initials: MR
authors.lastname: Bowman
authors.forename: B M
authors.initials: BM
authors.lastname: Carreno
authors.forename: M
authors.initials: M
authors.lastname: Collins
authors.forename: C R
authors.initials: CR
authors.lastname: Wood
authors.forename: T
authors.initials: T
authors.lastname: Honjo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000145:classification / Q000235:genetics / Q000276:immunology*; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen / Q000145:classification / Q000235:genetics / Q000276:immunology*; D051940:B7-2 Antigen; D001483:Base Sequence; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002455:Cell Division; D018076:DNA, Complementary; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000145:classification / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology
chemical_list: D015703:Antigens, CD; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D017252:CD3 Complex; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D018076:DNA, Complementary; D008024:Ligands; D008562:Membrane Glycoproteins; C105992:PDCD1 protein, human; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor