NK cell recognition of hematopoietic cells by SLAM-SAP families

The signaling lymphocyte activation molecule (SLAM) family of receptors (SFRs) are ubiquitously expressed on immune cells, and they regulate multiple immune events by recruiting SH2 (Src homology 2) domain-containing SAP family adapters, including SAP and its homologs, Ewing's sarcoma-associated transcript 2 (EAT-2) and EAT-2 related transducer (ERT). In human patients with X-linked lymphoproliferative (XLP) disease, which is caused by SAP mutations, SFRs alternatively bind other inhibitory SH2 domain-containing molecules to suppress immune cell activation and development. NK cells express multiple SFRs and all SAP family adapters. In recent decades, SFRs have been found to be critical for enhancing NK cell activation in response to abnormal hematopoietic cells in SAP-family-intact NK cells; however, SFRs might suppress NK cell activation in SAP-family-deficient mice or patients with XLP1. In this paper, we review how these two distinct SFR signaling pathways orchestrate NK cell activation and inhibition and highlight the importance of SFR regulation of NK cell biology and their physiological status and pathological relevance in patients with XLP1.