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 Ritchie, Marco Colonna, Daniel M Andrews, Mark J Smyth

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247 Citations (Scopus)


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
Original languageEnglish
Pages (from-to)431 - 438
Number of pages8
JournalNature Immunology
Issue number5
Publication statusPublished - 2014

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