NK Cell Regulation by SLAM Family Receptors and SAP-related Adapters

Signaling lymphocytic activating molecule (SLAM) family receptors and SLAM-associated protein (SAP)-related adapters play several important roles in the immune system. Natural killer (NK) cells express at least three members of the SLAM family. They are 2B4, NK, T- and B-cell antigen (NTB-A), and CD2-like receptor-activating cytotoxic cells (CRACC), which recognize their respective ligands CD48, NTB-A, and CRACC on target cells and possibly on other NK cells. In mature human NK cells, SLAM family receptors appear to have activating functions. In mature mouse NK cells, however, the only available information is for 2B4, which reportedly has the capacity to either stimulate or inhibit NK cell activation. The ability of SLAM family receptors to regulate NK cell functions seems to be largely dependent on their capacity to associate, by way of their cytoplasmic domain, with members of the SAP family of adapters, including SAP, Ewing's sarcoma-activated transcript-2 (EAT-2), and EAT-2-related transducer (ERT). By binding to SAP, SLAM family receptors are coupled to the Src kinase FynT, thereby evoking protein tyrosine phosphorylation signals. In human NK cells, SAP is likely to be crucial for the activating function of 2B4 and NTB-A but not of CRACC and also crucial for the activating function of 2B4 in mouse NK cells. EAT-2. SAP is ERT link SLAM family receptors to distinct, albeit poorly understood, signals. These two SAP-related adapters may be implicated in the inhibitory function of 2B4 observed in mouse NK cells. While much work remains to be carried out to fully understand the roles and mechanisms of action of the SLAM and SAP families in human and mouse NK cells, the published findings clearly establish that these molecules have important functions in NK cell biology.