title: The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions.
abstract: CD96, CD226 (DNAM-1) and TIGIT belong to an emerging family of receptors that interact with nectin and nectin-like proteins. CD226 activates natural killer (NK) cell-mediated cytotoxicity, whereas TIGIT reportedly counterbalances CD226. In contrast, the role of CD96, which shares the ligand CD155 with CD226 and TIGIT, has remained unclear. In this study we found that CD96 competed with CD226 for CD155 binding and limited NK cell function by direct inhibition. As a result, Cd96(-/-) mice displayed hyperinflammatory responses to the bacterial product lipopolysaccharide (LPS) and resistance to carcinogenesis and experimental lung metastases. Our data provide the first description, to our knowledge, of the ability of CD96 to negatively control cytokine responses by NK cells. Blocking CD96 may have applications in pathologies in which NK cells are important.
authors.affiliation: 1] Cellular Immunity Laboratory, Cancer Immunology Program, Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. [2] Department of Immunology, Monash University, Alfred Medical Research and Education Precinct, Prahran, Australia. [3].
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Chan
authors.affiliation: 1] Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia. [2].
authors.forename: Ludovic
authors.initials: L
authors.lastname: Martinet
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Gilfillan
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.
authors.forename: Fernando
authors.initials: F
authors.lastname: Souza-Fonseca-Guimaraes
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.
authors.forename: Melvyn T
authors.initials: MT
authors.lastname: Chow
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.
authors.forename: Liam
authors.initials: L
authors.lastname: Town
authors.affiliation: 1] Hematology Immunology Translational Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. [2] Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: David S
authors.initials: DS
authors.lastname: Ritchie
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.affiliation: 1] Cellular Immunity Laboratory, Cancer Immunology Program, Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. [2] Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Andrews
authors.affiliation: 1] Cellular Immunity Laboratory, Cancer Immunology Program, Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. [2] Department of Immunology, Monash University, Alfred Medical Research and Education Precinct, Prahran, Australia. [3] Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia. [4] Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. [5] School of Medicine, University of Queensland, Herston, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000075983:Nectins; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000276:immunology; D011014:Pneumonia / Q000276:immunology; D011485:Protein Binding / Q000235:genetics; D011971:Receptors, Immunologic / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; C116131:CD96 antigen; D015815:Cell Adhesion Molecules; D008070:Lipopolysaccharides; D000075983:Nectins; D011971:Receptors, Immunologic; D011991:Receptors, Virus; C556305:T cell Ig and ITIM domain protein, mouse; C066100:poliovirus receptor