The signaling lymphocyte activation molecule (SLAM) family, a subset of CD2 family, modulates the activity of a wide range of immune cell types, including T cells, B cells, macrophages, DCs and natural killer (NK) cells. The SLAM receptor-ligand interactions involving these immune cells control a variety of immune responses including T cell activation, memory-B-cell generation, antibody production and NK-cell activation. Currently, the SLAM family contains nine members: SLAM (CD 150), CD84, NK-T-B-A antigen (NTB-A), 2B4 (CD244), CD48, Ly-9 (CD229), CD2-like receptor activating cytotoxic T cells (CRACC), B-lymphocyte activator macrophage expressed (BLAME) and CD84-H1 (SF2001). The genes encoding SLAM family members, except for BLAME and SF2001, are tightly clustered on human chromosome 1 at lq23 and mouse chromosome 1 at 1H2. The CD2 family, which also includes CD2 and CD58, is located on chromosome 1 at lpl3 in humans. In mice CD2 is located on chromosome 3, and there is no CD58 homologue. All SLAM family members share a similar ectodomain organization, with an N-terminal membrane-distal IgV and a membrane-proximal truncated IgC2 domain; the sole exception is the ectodomain of Ly-9, which is composed of a tandem repeat of IgV-IgC2. Although the extracellular domains of CD2 and CD58 share similar organization with SLAM-family receptors, the sequence identity between these two receptors and SLAM-family receptors is less than 15%. It is notable that the binding partners of all characterized SLAM/CD2 family members are within the SLAM family. Both homophilic and heterophilic ligand-receptor interactions (e.g. 2B4 with CD48; CD2 with CD58) occur via their IgV domains.
All SLAM-family receptors contain two types of immunoreceptor tyrosine based switch motifs (ITSMs), TIYxxV/I or TVYxxV/I, in their cytoplasmic tails. Phosphorylated ITSMs can serve as docking sites for the SLAM-associated protein (SAP), as well as the related Ewing's sarcoma-associated transcript (EAT)-2 and EAT-2- related transducer (ERT) proteins. The association between ITSMs from SLAM family receptors and SAP family adaptors appears to be critical for the SLAM family receptors to transmit signals upon engagement.
The signaling through SLAM family receptors appears to cooperate in the development of natural killer T (NKT) and CD4+ T cells. T and natural killer T (NKT) cell lineages arise from common precursors upon interaction with ligand-expressing cells in the thymus. During the NKT cell development, the primary signals come from the interaction between TCR from NKT cell precursors and CD Id ligands from cortical thymocytes. In addition, a second signal, which is mediated by the engagement of the homophilic receptors CD150 and NTB-A and the downstream recruitment of the adaptor SLAM-associated protein (SAP) and the Src kinase Fyn, is required for the NKT cell lineage development. Similar to NKT cells, the signaling molecules SAP, Fyn, and PKC0 are essential for CD4 T cell development. Thus, SLAM-SAP signaling pathway is utilized by both CD4 T cell and NKT cells for their development and function.
SAP and SAP associated proteins
The SAP family comprises SAP, EAT-2 (also known as SH2D1B) and ERT (also known as SH2D1C). All three members contain an SH2 domain and a short C-terminal tail. The protein sequence similarities and gene localization suggest that EAT-2 and ERT are closely related to each other and were probably generated by gene duplication. SAP is expressed in T cells, NK cells, NKT cells, eosinophils, platelets and some B cells, whereas EAT-2 is expressed in NK cells, DCs and macrophages. ERT is expressed only in the mouse NK cells. The wide ex
The role of SAP was first associated with immune regulation when mutations in the gene encoding SAP were found in X-linked lymphoproliferative (XLP) disease, a human immunodeficiency disease characterized by a dysregulated immune response to infection by Epstein Barr virus (EBV). The SAP mutations found in XLP are diverse, ranging from large deletions to point mutations in the gene. As a consequence of these mutations, the SAP protein either is not expressed or loses its functions.
Signaling pathways associated with the SLAM-family receptors operate through the SAP and EAT-2. The SH2 domain of SAP contacts the ITSM of a SLAM-family member. This recognition appears to be insensitive to the phosphorylation status of the target protein. In addition, SAP also binds to the SH3 domain of a tyrosine kinase Fyn via its C-terminal arginine based motif. These unique binding properties allow SAP to function as an adaptor molecule that bridges the cytoplasmic domains of the SLAM family receptors and Fyn. Formation of the SLAM-SAP-Fyn ternary complex triggers a signaling cascade that results in phosphorylation of SHIP, Dokl, Dok2 and She, ultimately inhibiting the IFN-y secretion in T cells. A similar SAP-Fyn pathway enhances cytotoxicity of NK cells against tumor cells. Similar to that of SAP, the SH2 domain of EAT-2 can also recognize the conserved ITSM in SLAM family. However, as EAT-2 lacks the SH3 recognition motif present in SAP, EAT-2 cannot bind the SH3 domain of Fyn. The exact biochemical mechanism of lymphocyte regulation by EAT-2 is not clear, but it appears to be associated with the phosphorylation state of two tyrosines at the C-terminus of EAT-2. The wide cell type distribution of the SLAM receptor and SAP adaptor families suggests that these proteins are involved in a wide range of immune functions.
Polymorphisms of SLAM family
Several studies have indicated that extensive polymorphisms within SLAM family genes contribute to the susceptibility to the autoimmune disease, systemic lupus erythematosis (SLE). An Slelb locus, which was identified in a spontaneous lupus mouse model NZW strain, was found to be the most potent susceptibility locus for SLE because the C57BL/6 congenic strain carrying this gene segment exhibits penetrant anti-nuclear autoantibody production. Sequence comparison at this locus between C57BL/6 and NZW-derived variants revealed that polymorphisms in the SLAM family receptor genes contribute to the pathogenesis of SLE. In addition, two isoforms of NTB-A transcripts were identified in the context of the C57BL/6 background. The long isoform of murine NTB-A (or Ly-108), Ly 108-1 is up-regulated, while the longer isoform (Lyl08-2) is down-regulated in B6.Slelb mice compared with C57BL/6. Transfection with a Ly 108-2 construct sensitizes an immature B cell line to undergo apoptosis, suggesting that Lyl08 may censor self-reactive B cells and prevent against autoimmunity. These results suggest NTB-A may be the strongest candidate to be causally correlated with the B6.Slelb phenotype.