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  • Review Article
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Immune regulation by SLAM family receptors and SAP-related adaptors

Nature Reviews Immunology volume 6, pages 56–66 (2006)Cite this article

Key Points

  • There is increasing evidence that SLAM family receptors and SAP-related adaptors play important and complex roles in normal immune regulation.

  • SLAM family receptors associate through their cytoplasmic domain with the SRC homology 2 (SH2) domain of SAP-related adaptors. This association is crucial for SLAM family receptor functions.

  • The SAP gene is mutated and inactivated in X-linked lymphoproliferative (XLP) disease, a human immunodeficiency characterized by an abnormal immune response to Epstein?Barr virus (EBV) infection.

  • XLP seems to result from defective cytotoxic activity towards EBV-infected cells, due to reduced SLAM family receptor functions in natural killer (NK) cells and, perhaps, CD8+ T cells. Defects in NKT cells might also be implicated.

  • Experiments with SAP-deficient humans and mice showed that SAP and, presumably, SLAM family receptors are also required for T helper 2 (TH2)-cell priming, immunoglobulin isotype switching and maintenance of long-term antibody-secreting cells.

  • SAP operates as a result of its capacity to couple SLAM-related receptors to the SRC family kinase FYNT, by way of a second binding surface centered on arginine 78 in the SAP SH2 domain that interacts directly with the SH3 domain of FYNT. The resulting tyrosine phosphorylation signals enable SLAM family receptors to augment responses such as NK-cell activation and TH2-cell priming.

  • In contrast to SAP, the SAP-related adaptors EAT2 and ERT signal by way of tyrosine phosphorylation sites in their C-terminal tail. In NK cells, these signals allow SLAM family receptors to inhibit NK-cell activation.

  • Differential binding of SLAM family receptors to SAP or EAT2 and ERT enables these receptors to mediate alternative and, at least in some cases, opposite immune functions.

Abstract

The signalling lymphocytic activation molecule (SLAM) family of receptors is expressed by a wide range of immune cells. Through their cytoplasmic domain, SLAM family receptors associate with SLAM-associated protein (SAP)-related molecules, a group of cytoplasmic adaptors composed almost exclusively of an SRC homology 2 domain. SAP, the prototype of the SAP family, is mutated in a human immunodeficiency named X-linked lymphoproliferative (XLP) disease. Recent observations indicate that SLAM family receptors, in association with SAP family adaptors, have crucial roles during normal immune reactions in innate and adaptive immune cells. The latest progress in this field is reviewed here.

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Figure 1: Immunoreceptors and their functions.
Figure 2: Structure, chromosomal localization and expression pattern of SAP-related adaptors.
Figure 3: Mechanism of action of SAP and EAT2.
Figure 4: SLAM-mediated regulation of T helper 2 cytokine production.
Figure 5: A possible model for the stimulatory and inhibitory functions of 2B4.
Figure 6: SAP-dependent functions in immune regulation.

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Acknowledgements

I apologize for not being able to cite and discuss all papers published on this topic, owing to space limitation. I thank M.-C. Zhong, M.-E. Cruz-Munoz, R. Roncagalli, R. Chen and D. Davidson for reading of the manuscript. Work in my laboratory is supported by grants from the Canadian Institutes of Health Research, the National Cancer Institute of Canada and the CANVAC National Centre of Excellence. I am the recipient of the Canada Research Chair in Signalling in the Immune System.

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  1. Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, H2W 1R7, Quebec, Canada

    André Veillette

  2. Department of Medicine, University of Montreal, Montreal, H3C 3J7, Quebec, Canada

    André Veillette

  3. Department of Medicine, McGill University, 3655 Promenade Sir William Osler, Montreal, H3G 1Y6, Quebec, Canada

    André Veillette

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DATABASES

Genetic disease information

X-linked lymphoproliferative (XLP) disease

Glossary

Immunoreceptor tyrosine-based activation motif

(ITAM). A sequence that is present in the cytoplasmic domains of the invariant chains of various cell-surface immune receptors, such as the T-cell receptor, the B-cell receptor, the receptor for IgE (FcεR) and natural-killer-cell activating receptors. Following phosphorylation of their tyrosine residues, ITAMs function as docking sites for SRC homology 2 (SH2)-domain-containing tyrosine kinases, thereby favouring intracellular-signalling cascades.

ZAP70/SYK

A family of cytoplasmic protein tyrosine kinases implicated in the amplification of immunoreceptor signalling. By way of tandem SRC homology 2 (SH2) domains at their N-terminus, they interact with immunoreceptor tyrosine-based activation motifs (ITAMs) that are doubly tyrosine phosphorylated.

BTK family

A class of cytoplasmic protein tyrosine kinases involved in the amplification of immunoreceptor signalling. It includes BTK, ITK, TEC, RLK and BMX. Most are recruited to the plasma membrane through interaction of their N-terminal pleckstrin homology domain with phosphatidylinositol-3,4,5-trisphosphate, which is generated on activation of phosphatidylinositol 3-kinase.

SRC homology 2 (SH2) domain

Domain of ∼100 amino acids found in a variety of enzymes and adaptor molecules. It controls multiple signalling processes by interacting with phosphotyrosine-containing motifs.

Infectious mononucleosis

Illness typically induced by Epstein?Barr virus (EBV). It is normally a self-contained episode of sore throat, fever, and enlargement of spleen (splenomegaly) and lymph nodes (lymphadenopathy).

Common variable immunodeficiency

(CVID). A disease characterized by a deficiency in various immunoglobulins including IgM, IgG and IgA. Some cases are inherited, whereas others are sporadic. In most cases, the cause is unknown. Patients with CVID have an increased susceptibility to infections.

T-cell-dependent antigens

Antigens that require T-cell help to trigger antibody production by B cells.

T-cell-independent antigens

Antigens, usually microbial in nature, that do not require T cells to trigger antibody production by B cells. This is because of the ability of the microbial constituents to stimulate B cells directly through pathogen-associated determinants such as bacterial lipopolysaccharide.

Immunoglobulin circular transcripts

RNA transcripts produced by 'looped-out' DNA segments during the immunoglobulin gene recombination events leading to isotype switching.

Immunoglobulin-like domain

Domain with two β-sheets linked by disulphide bonds reminiscent of the structure of immunoglobulins. It is present in several proteins involved in cell?cell interactions.

Morbillivirus

Viral genus of the Paramyxoviridae family. It includes measles virus (in humans), canine distemper virus (in dogs) and rinderpest virus (in cows). Morbilliviruses mainly infect lymphoid cells. Several members of the genus use signalling lymphocytic activation molecule (SLAM) for entry into lymphoid cells.

SRC homology 3 (SH3) domain

Domain of ∼60 amino acids present in signalling molecules, including enzymes and adaptors. It binds proline-rich sequences and, in some cases, arginine-based motifs.

SRC family

A class of cytoplasmic protein tyrosine kinases involved in the initiation of immunoreceptor signalling. It includes LCK, FYNT, LYN, HCK, BLK, C-YES, C-SRC, C-FGR and YRK.

Pristane-induced auto-antibody production

Pristane is an isoprenoid alkane capable of inducing lupus-like diseases in mice. Manifestations include auto-antibody production and renal inflammation (glomerulonephritis).

NZM2410

Mouse strain that is highly prone to spontaneous lupus. Several genetic loci named Sle1a, Sle1b and so on seem implicated in this increased susceptibility.

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Veillette, A. Immune regulation by SLAM family receptors and SAP-related adaptors. Nat Rev Immunol 6, 56–66 (2006). https://doi.org/10.1038/nri1761

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