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PMID: 24658051 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions.

Nature immunology ·Vol. 15 ·No. 5 ·2014-05-00 ·Pages 431-8

Chan CJ, Martinet L, Gilfillan S, Souza-Fonseca-Guimaraes F, Chow MT, Town L, Ritchie DS, Colonna M, Andrews DM, Smyth MJ

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.

MeSH Terms
Animals Antigens, CD/genetics,metabolism Antigens, Differentiation, T-Lymphocyte/genetics,metabolism Cell Adhesion Molecules/metabolism Cells, Cultured Cytotoxicity, Immunologic/genetics Killer Cells, Natural/immunology Lipopolysaccharides/immunology Lung Neoplasms/immunology Mice Mice, Inbred C57BL Mice, Knockout Nectins Neoplasm Metastasis Neoplasms, Experimental/immunology Pneumonia/immunology Protein Binding/genetics Receptors, Immunologic/metabolism Receptors, Virus/metabolism
Chemicals
Antigens, CD Antigens, Differentiation, T-Lymphocyte CD226 antigen CD96 antigen Cell Adhesion Molecules Lipopolysaccharides Nectins Receptors, Immunologic Receptors, Virus T cell Ig and ITIM domain protein, mouse poliovirus receptor
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Chan Christopher J
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].
Martinet Ludovic
1] Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia. [2].
Gilfillan Susan
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
Souza-Fonseca-Guimaraes Fernando
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.
Chow Melvyn T
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.
Town Liam
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.
Ritchie David S
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.
Colonna Marco
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
Andrews Daniel M
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.
Smyth Mark J
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.
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Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.2850
Published
2014-05-00
Epub
2014-00-23
Pages
431-8
Language
English
Region
United States
NLM ID
100941354
Subset
IM
Grants
NIAMS NIH HHS · P30AR048335 · United States
Corrections
CommentIn
PMID: 24705706
CommentIn
PMID: 24747702
External Links
PubMed source DOI: 10.1038/ni.2850 View journal details
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