DNAM-1 (CD226) is a member of the immunoglobulin superfamily and is expressed on the majority of NK cells, T cells, monocytes, and platelets. DNAM-1 constitutively associates with LFA-1 on NK cells. Ligation of LFA-1 with antibodies causes Fyn-dependent phosphorylation of tyrosine residues in the cytoplasmic domain of DNAM-1, which are necessary for DNAM-1–dependent NK cell functions. DNAM-1 also associates with LFA-1 in activated T cells, for which the protein kinase C–induced serine phosphorylation in the cytoplasmic domain of DNAM-1 is responsible, and is involved in an LFA-1–mediated costimulatory signal for naive T cell differentiation and proliferation. The poliovirus receptor (PVR) CD155 and its family member CD112 (PRR-2 [PVR-related family 2], also called nectin-2) are ligands for human and mouse DNAM-1. Interactions between DNAM-1 on NK cells and T cells and its ligands CD112 and CD155 on cancer cells augment cell-mediated cytotoxicity and cytokine production. Although human CD112 and CD155 are broadly distributed on epithelial and endothelial cells in many tissues, they are overexpressed on certain tumors, both nonhematopoietic and hematopoietic, including colorectal carcinomas, gastric cancers, ovarian cancers, neuroblastomas, myeloid leukemias, and multiple myeloma, suggesting that DNAM-1 ligand expression might be induced by tumorigenesis and, thus, stimulates CTL and NK cells.
Iguchi-Manaka A, Kai H, Yamashita Y, et al. Accelerated tumor growth in mice deficient in DNAM-1 receptor. The Journal of Experimental Medicine. 2008;205(13):2959-2964.