DNAM-1 control of natural killer cells functions through nectin and nectin-like proteins

Natural killer (NK) cells represent key innate immune cells that restrain viral infection and malignant transformation and help mount an adaptive immune response. To perform such complicated tasks, NK cells express a wide set of inhibitory and activating receptors that alert them against cellular stress without damaging healthy cells. A new family of receptors that recognize nectin and nectin-like molecules has recently emerged as a critical regulator of NK cell functions. The most famous member of this family, DNAX accessory molecule (DNAM-1, CD226), is an adhesion molecule that control NK cell cytotoxicity and interferon-γ production against a wide range of cancer and infected cells. Its ligands CD112 and CD155 have been described in different pathological conditions, and recent evidence indicates that their expression is regulated by cellular stress. Additional receptors have been shown to bind DNAM-1 ligands and modulate NK cell functions bringing another level of complexity. These include CD96 (TACTILE) and TIGIT (WUCAM, VSTM3). Here, we review the role of DNAM-1, TIGIT and CD96 in NK cell biology summarizing the recent advances made on the role of these receptors in various pathologies, such as cancer, viral infections and autoimmunity.