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

Christopher J Chan; Ludovic Martinet; Susan Gilfillan; Fernando Souza-Fonseca-Guimaraes; Melvyn T Chow; Liam Town; David S Ritchie; Marco Colonna; Daniel M Andrews; Mark J Smyth

doi:10.1038/ni.2850

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

Nat Immunol. 2014 May;15(5):431-8. doi: 10.1038/ni.2850. Epub 2014 Mar 23.

Authors

Affiliations

¹ 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].
² 1] Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia. [2].
³ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
⁴ Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.
⁵ 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.
⁶ 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.
⁷ 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.

PMID: 24658051
DOI: 10.1038/ni.2850

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, CD / genetics
Antigens, CD / metabolism*
Antigens, Differentiation, T-Lymphocyte / genetics
Antigens, Differentiation, T-Lymphocyte / 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

Substances

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

Grants and funding

P30AR048335/AR/NIAMS NIH HHS/United States