SLAM Family Receptor Signaling in Viral Infections: HIV and Beyond

Abstract

The signaling lymphocytic activation molecule (SLAM) family of receptors are expressed on the majority of immune cells. These receptors often serve as self-ligands, and play important roles in cellular communication and adhesion, thus modulating immune responses. SLAM family receptor signaling is differentially regulated in various immune cell types, with responses generally being determined by the presence or absence of two SLAM family adaptor proteins—Ewing’s sarcoma-associated transcript 2 (EAT-2) and SLAM-associated adaptor protein (SAP). In addition to serving as direct regulators of the immune system, certain SLAM family members have also been identified as direct targets for specific microbes and viruses. Here, we will discuss the known roles for these receptors in the setting of viral infection, with special emphasis placed on HIV infection. Because HIV causes such complex dysregulation of the immune system, studies of the roles for SLAM family receptors in this context are particularly exciting.

SLAMF7 Signaling Reprograms T Cells toward Exhaustion in the Tumor Microenvironment

“…The SLAMF7 (CRACC, CD319, CS-1) receptor is a member of the signaling lymphocytic activation molecules (SLAM) family of receptors (21), with expression restricted to hematopoietic cells, and is present at differing frequencies on various types of immune cells (21)(22)(23). SLAMF7, and other SLAM family members (except 2B4), are unique in that they function as homotypic receptors, which once activated, recruit various SH2 domain-containing proteins to their cytoplasmic immunoreceptor tyrosine-based switch motifs (21,24).…”

Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): A multicenter, retrospective study

“… 15 SH2D1B is a unique adaptor protein that enhances innate and adaptive immune responses to antigens. 16 , 17 In this regard, the SH2D1B signaling pathway has the potential to be co-opted to produce enhanced vaccination responses. 16 CUL2 is a mediator of inflammation and, in this regard, its pharmacological inhibition protects against hyperinflammatory responses, 18 a finding that could be relevant for those MIS-C patients that do not respond to the standard treatment.…”

Adenoviral delivery of an immunomodulatory protein to the tumor microenvironment controls tumor growth

“…Cell type-specific, single-cell predictions of the function of Ad-SF7-Fc in vivo Because SLAMF7 is a homotypic receptor, and since SF7-Fc is composed of the extracellular domain of SLAMF7, SF7-Fc can conceivably function to both activate and/or block SLAMF7 signaling, depending on local environmental factors and the cell type in question. Additionally, activating or blocking SLAMF7 can have vastly different outcomes on different cell types depending on the presence of EAT-2, 9,11 which may mechanistically explain how Ad-SF7-Fc achieves tumor control. Therefore, we devised an approach using high dimensional spectral cytometry, which allowed us to predict if SF7-Fc was activating or blocking SLAMF7 at the single-cell level (Figure 7A; see materials and methods).…”

“…The signaling lymphocytic activation molecule family member 7 (SLAMF7) (CRACC, CD319, CS-1) is a self-ligand receptor, restricted to hematopoietic cells and expressed at varying frequencies on different immune cell subsets. [8][9][10] SLAMF7 is capable of mediating both activating and inhibitory signals in immune cells; a distinction largely dependent on the presence of its adaptor protein, Ewing's sarcoma-associated transcript 2 (EAT-2). 11 When SLAMF7 is activated in the presence of EAT-2, EAT-2 binds to SLAMF7's phosphorylated intracellular immunoreceptor tyrosine-based switch motif (ITSM) and mediates immune cell activation, while in the absence of EAT-2, various inhibitory SH2 domain-containing phosphatases are recruited to SLAMF7's ITSM.…”