SLAM-family receptors: immune regulators with or without SAP-family adaptors

Abstract

The signaling lymphocytic activation molecule (SLAM) family of receptors and the SLAM-associated protein (SAP) family of intracellular adaptors are expressed in immune cells. By way of their cytoplasmic domain, SLAM-related receptors physically associate with SAP-related adaptors. Evidence is accumulating that the SLAM and SAP families play crucial roles in multiple immune cell types. Moreover, the prototype of the SAP family, that is SAP, is mutated in a human immunodeficiency, X-linked lymphoproliferative (XLP) disease. In the presence of SAP-family adaptors, the SLAM family usually mediates stimulatory signals that promote immune cell activation or differentiation. In the absence of SAP-family adaptors, though, the SLAM family undergoes a "switch-of-function," thereby mediating inhibitory signals that suppress immune cell functions. The molecular basis and significance of this mechanism are discussed herein.

Figure 1.

Triggering of SLAM-family receptors by heterotypic or homotypic cell–cell interactions. All SLAM-family receptors, except 2B4, are self-ligands. In the case of 2B4, the ligand is CD48, another receptor expressed on hematopoietic cells. Consequently, SLAM-family receptors can be triggered during heterotypic or homotypic cell–cell interactions. (A) Heterotypic cell–cell interactions. Triggering of 2B4 on natural killer cells (NK) by CD48 on target cells results in SAP family adaptor-dependent signals, which enhance cytotoxicity and interferon (IFN)-γ secretion induced through stimulation of the primary activating receptor NKG2D by its ligand Rae-1. (B) Homotypic cell–cell interactions. Triggering of Ly108 by Ly108 on two double-positive thymocytes (DP) results in SAP-dependent signals, which promote positive selection and/or proliferation of DP expressing the appropriate T cell receptor (TCR) and engaged by self-lipid-loaded CD1d.

Figure 2.

SAP-related adaptors mediate active biochemical signals. Through intrinsic mechanisms, SAP-family adaptors can couple SLAM-family receptors to active signals. (A) SAP. Via its Src homology 2 (SH2) region, SAP associates with a phosphorylated tyrosine-based motif (pY) in SLAM-related receptors (SLAM). By way of the arginine 78-based motif in its SH2 domain, SAP simultaneously binds to the Src family protein tyrosine kinase Fyn, through the Fyn Src homology 3 (SH3) domain. This allows SAP to couple SLAM-related receptors to protein tyrosine phosphorylation signals. (B) EAT-2. Like SAP, EAT-2 (and probably ERT; not shown) associates with a phosphorylated tyrosine-based motif (pY) in SLAM-related receptors (SLAM), through the EAT-2 SH2 domain. Via one or two phosphorylated tyrosines located in its carboxy-terminal tail, EAT-2 concomitantly interacts with its effectors. Although the identity of these effectors is not well defined, recent data suggested that phospholipase C (PLC)-γ may be involved.

Figure 3.

“Switch-of-function” of SLAM-family receptors in the absence of SAP-family adaptors. (A) In the presence of SAP-family adaptors, SLAM-family receptors (2B4 is depicted here) mediate positive signals that promote natural killer cell (NK) activation by target cells. This is because SAP family adaptor-mediated signals dominate over signals mediated by inhibitory effectors, which are proposed to bind a tyrosine-based motif distinct from the one interacting with SAP-related adaptors. (B) In the absence of SAP-family adaptors, however, SLAM-family receptors mediate negative signals that inhibit natural killer cell (NK) activation by target cells. This is because inhibitory signals dominate.