SLAM family receptors and the SLAM-associated protein (SAP) modulate T cell functions

Abstract

One or more of the signaling lymphocytic activation molecule (SLAM) family (SLAMF) of cell surface receptors, which consists of nine transmembrane proteins, i.e., SLAMF1-9, are expressed on most hematopoietic cells. While most SLAMF receptors serve as self-ligands, SLAMF2 and SLAMF4 use each other as counter structures. Six of the receptors carry one or more copies of a unique intracellular tyrosine-based switch motif, which has high affinity for the single SH2-domain signaling molecules SLAM-associated protein and EAT-2. Whereas SLAMF receptors are costimulatory molecules on the surface of CD4+, CD8+, and natural killer (NK) T cells, they also involved in early phases of lineage commitment during hematopoiesis. SLAMF receptors regulate T lymphocyte development and function and modulate lytic activity, cytokine production, and major histocompatibility complex-independent cell inhibition of NK cells. Furthermore, they modulate B cell activation and memory generation, neutrophil, dendritic cell, macrophage and eosinophil function, and platelet aggregation. In this review, we will discuss the role of SLAM receptors and their adapters in T cell function, and we will examine the role of these receptors and their adapters in X-linked lymphoproliferative disease and their contribution to disease susceptibility in systemic lupus erythematosus.

Fig. 1

SLAM family receptors in the immune synapse. The mostly homophilic interactions between SLAMF receptors subserve their role as costimulatory molecules. The binding of the SLAMF receptors to their ligands induces tyrosine phosphorylation of ITSM motifs in their cytoplasmic tail to which the adapters SAP or EAT-2 bind subsequently. SAP is mostly expressed by T cells, whereas EAT-2 is primarily expressed in APC

Fig. 2

Cytoplasmic tails of human SLAM receptors and the functional ITSM motifs and other docking sites. Cytoplasmic tails of human full-length SLAMF1 and SLAMF3-7 contain several ITSM motifs (tyrosine (Y) in red) which are docking sites for the SAP and EAT-2 adapters. Additional tyrosines are in the cytoplasmic tail of the SLAMF molecules (Y in black) are involved in the association with other effector molecules, e.g., SLAMF3 binds to the adaptor molecules AP-2 and Grb-2. Numbers indicate the tyrosine position relative to the molecule's N-terminal amino acid accession numbers between brackets correspond to Ensembl ID

Fig. 3

A model depicting how apoptosis in CD8+ T cells is controlled by SAP in a Fyn-dependent and Fyn-independent manner. Signaling of SLAMF receptors through SAP binding and subsequent recruitment of Fyn fine-tunes the strength of the TCR signals and contributes in the p73-mediated way of apoptosis during primary T cell responses. In this model, activated Fyn could block the ubiquitin ligase Itch and therefore inhibit the degradation of p73. During the re-activation phase of T cells, SLAMF receptors, e.g., SLAMF6, might promote apoptosis by a SAP-dependent but Fyn-independent mechanism. In this model, SAP dislodges the phosphatase SHP1 from the cytoplasmic tail of SLAM molecules, which facilitates a stronger level of TCR signals sufficient to induce the transcription of RICD mediators such as FasL and Bim. Rectangles: intracellular signaling molecules, ellipses: membrane receptors or their secreted forms (FasL)

Fig. 4

Signal transduction by SLAM family surface receptors in CD4+ T cells. During formation of the immune synapse, clustering of SLAMF receptors brings SAP to its cytoplasmic tails and mediates recruitment and activation of Fyn. Thus, SLAMF receptors modulate TCR signaling by inducing a sustained recruitment of PKCθ and Bcl-10, which in turn leads to the activation of NF-κB and consequently to the production of Th2 cytokines and participation in NKT/innate CD4 T cell development. Phosphorylated tyrosines in the SLAMF cytoplasmic tails triggers the association with SHIP, docking protein 1 (DOK1), DOK2, and RAS-GAP, which may participate in these processes