Scaffolding of SLAM Receptor Signaling

A small group of receptors implicated in immune cell regulation are members of the signaling lymphocytic activation molecule (SLAM) family, which belongs to the CD2 subfamily of Ig receptors. These include SLAM (CD150), 2B4, CD84, NTBA (NK-,T- and B-cell antigen), Ly9 (CD229) and CD2-like receptor activating cytotoxic cells or CRACC (CD319) (Ma et al. 2007; Veillette 2006). They have Ig-like domains in their extracellular regions and are expressed in different subsets of lymphocytes. Except for 2B4, which binds CD48, the ligands for SLAM receptors are not well characterized, but almost all members of the family appear to be involved in homotypic interaction with other SLAM expressing cells. SLAM/ CD150 is expressed on thymocytes, T cells, B cells, macrophages and dendritic cells and interestingly serves as the lymphoid specific receptor for morbilliviruses (including measles) (Tatsuo et al. 2000; Veillette 2006). T cells from SLAM-deficient mice have a defect in the production of IL-4 and IL-13, but not INF-y, suggesting that SLAM is involved in skewing the immune response towards a Th2 response (Davidson et al. 2004; Wang et al. 2004). Furthermore, SLAM is thought to be involved in the communication between T cells and antigen-presenting cells (APCs) in vivo, and SLAM expression is upregulated on APCs after inflammatory stimuli (Bleharski et al. 2001; Kruse et al. 2001). However, further work is required to fully understand the role of SLAM interactions in immune development and regulation.

A common denominator of the SLAM family of receptors is their ability to interact with a small family of adaptors called SLAM-associated proteins or SAPs (Ma et al. 2007; Veillette 2006). The three members of this family are SAP, Ewing's sarcoma-associated transcript-2 (EAT-2) and the rodent member EAT-2-related transducer (ERT). They have a very simple structure consisting of an SH2 domain and a short C-terminal tail. The SH2 domain interacts with the consensus TxYxxV/I present in the cytoplasmic part of some, but not all forms of SLAM receptors. In contrast to classical SH2 domain interactions, SAP can bind to this motif independently of tyrosine phosphorylation, suggesting that SAP constitutively interacts with SLAM receptors (Latour et al. 2001). This association to SAP makes the receptor able to signal through tyrosine phosphorylation by recruiting the Src kinase Fyn through a unique type of interaction (Chan et al. 2003; Latour et al. 2003). An arginine-based motif (RFFRKVKN) localized between the sixth P-sheet and the second a-helix of the SAP SH2-domain specifically interacts with the SH3 domain of Fyn. This means that this interaction occurs on the external surface away from the phosphotyrosine pocket interacting with the tyrosine-based motif of the SLAM receptors. The association with Fyn is induced upon receptor engagement and leads to activation of Fyn kinase activity and subsequent phosphorylation of additional tyrosine motifs present in the C-terminal part of the receptors. In the case of SLAM, this leads to the recruitment of the inositol phosphatase SHIP and assembly of a complex involving Dok1, Dok2 and RasGAP (Latour et al. 2001). Hence, the dual-binding capabilities of the SAP SH2 domain form a unique scaffolding module that alone connects the SLAM receptors to downstream signaling.

The identification of SAP (SH2D1A) as the aberrant gene that causes X-linked lymphoproliferative (XLP) syndrome clearly points to a central role of SAP in immune homeostasis (Coffey et al. 1998; Nichols et al. 1998; Sayos et al. 1998). XLP is a complex disorder characterized by a defect in immune regulation usually manifested by an uncontrolled immune response to primary infection of Epstein Barr virus (EBV). Other common clinical features are lymphoproliferative disorders and dysgammaglobulinemia. Importantly, the phenotype of SAP-deficient mice recapitulates several important aspects of the immune defect seen in XLP, including defects in Th2 cytokine production, hyper-responsive CD8+ population after virus infection, defects in B-cell function and absence of NKT cells (Ma et al. 2007). The lack of NKT cells in SAP-deficient mice is striking, since the development of T and NK cells appears normal. Interestingly, Fyn is also implicated in the development of NKT cells, suggesting that the SAP/Fyn signaling unit transmits signals necessary for this process. Furthermore, the Th2-cell defect seen in SLAM-deficient mice is reminiscent of the phenotype observed in SAP and Fyn-deficient mice, suggesting that SLAM primarily signals through SAP-Fyn. Together these data support a central role of the SLAM-SAP-Fyn signaling in the control of immune effector functions during infections.

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