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.


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


  • 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