title: Coinhibitory receptor PD-1H preferentially suppresses CD4⁺ T cell-mediated immunity.
abstract: T cell activation is regulated by the interactions of surface receptors with stimulatory and inhibitory ligands. Programmed death-1 homolog (PD-1H, also called VISTA) is a member of the CD28 family of proteins and has been shown to act as a coinhibitory ligand on APCs that suppress T cell responses. Here, we determined that PD-1H functions as a coinhibitory receptor for CD4⁺ T cells. CD4⁺ T cells in mice lacking PD-1H exhibited a dramatically increased response to antigen stimulation. Furthermore, delivery of a PD-1H-specific agonist mAb directly inhibited CD4⁺ T cell activation both in vitro and in vivo, validating a coinhibitory function of PD-1H. In a murine model of acute hepatitis, administration of a PD-1H agonist mAb suppressed CD4⁺ T cell-mediated acute inflammation. PD-1H-deficient animals were highly resistant to tumor induction in a murine brain glioma model, and depletion of CD4⁺ T cells, but not CD8⁺ T cells, promoted tumor formation. Together, our findings suggest that PD-1H has potential as a target of immune modulation in the treatment of human inflammation and malignancies.
authors.forename: Dallas B
authors.initials: DB
authors.lastname: Flies
authors.forename: Xue
authors.initials: X
authors.lastname: Han
authors.forename: Tomoe
authors.initials: T
authors.lastname: Higuchi
authors.forename: Linghua
authors.initials: L
authors.lastname: Zheng
authors.forename: Jingwei
authors.initials: J
authors.lastname: Sun
authors.forename: Jessica Jane
authors.initials: JJ
authors.lastname: Ye
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
mesh_terms: D000208:Acute Disease; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D017951:Antigen Presentation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D060887:B7 Antigens / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D005910:Glioma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006505:Hepatitis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D007111:Immunity, Cellular; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D060887:B7 Antigens
references.citation: Immunol Rev. 2009 May;229(1):307-21
references.pmid: 19426230
references.citation: Immunol Cell Biol. 1998 Dec;76(6):542-9
references.pmid: 9893032
references.citation: N Engl J Med. 2012 Jun 28;366(26):2455-65
references.pmid: 22658128
references.citation: Cancer Immunol Immunother. 2011 Feb;60(2):153-60
references.pmid: 21120655
references.citation: Nat Rev Drug Discov. 2013 Feb;12(2):130-46
references.pmid: 23370250
references.citation: Trends Mol Med. 2013 Sep;19(9):565-82
references.pmid: 23831337
references.citation: J Immunol. 2011 Aug 15;187(4):1537-41
references.pmid: 21768399
references.citation: J Exp Med. 2011 Mar 14;208(3):577-92
references.pmid: 21383057
references.citation: Radiat Res. 2011 Oct;176(4):459-73
references.pmid: 21787181
references.citation: Dose Response. 2006 Aug 28;5(1):39-47
references.pmid: 18648611
references.citation: PLoS One. 2012;7(2):e30852
references.pmid: 22347406
references.citation: Self Nonself. 2010 Jul;1(3):231-240
references.pmid: 21487479
references.citation: Clin Cancer Res. 2013 Oct 1;19(19):5300-9
references.pmid: 24089443
references.citation: Immunity. 2011 Apr 22;34(4):466-78
references.pmid: 21511182
references.citation: Clin Cancer Res. 2006 Aug 1;12(15):4730-7
references.pmid: 16899624
references.citation: Nat Rev Immunol. 2013 Apr;13(4):227-42
references.pmid: 23470321
references.citation: N Engl J Med. 2012 Jun 28;366(26):2443-54
references.pmid: 22658127
references.citation: Crit Rev Immunol. 2006;26(5):453-73
references.pmid: 17341188
references.citation: J Clin Invest. 1992 Jul;90(1):196-203
references.pmid: 1634608
references.citation: Nat Biotechnol. 2010 Jul;28(7):749-55
references.pmid: 20562862