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  • Review Article
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The SAP and SLAM families in immune responses and X-linked lymphoproliferative disease

Key Points

  • SAP (signalling lymphocytic activation molecule (SLAM)-associated protein) is a cytoplasmic protein that consists of a single SH2 domain with a 28-amino-acid tail.

  • The gene encoding SAP is defective or absent in patients with X-linked lymphoproliferative syndrome (XLP).

  • The three main disease manifestations of XLP are: fatal infectious mononucleosis, B-cell lymphoma and/or dysgammaglobulinaemia.

  • The SH2 domain of SAP binds with high affinity to the cytoplasmic domains of SLAM and five related cell-surface receptors (CD84, NTBA, CS1, CD229 and CD244) through a tyrosine-based motif Thr-Ile/Val-Tyr-Xaa-Xaa-Val/Ile.

  • SAP regulates signal transduction initiated by engagement of the SLAM-family receptors, in part, by recruiting SRC kinases, particularly FYN, which binds to SAP through its SH3 domain.

  • SAP can block the recruitment of SH2-domain-containing signal-transduction molecules.

  • Sap-deficient mice respond to infection with lymphocytic choriomeningitis virus (LCMV) by marked mobilization of interferon-γ (IFN-γ)-producing CD8+ and CD4+ T cells, reminiscent of the response by patients with XLP to Epstein–Barr virus.

  • Dysgammaglobulinaemia observed in Sap-deficient mice can be explained by an impaired formation of germinal centres caused by a defect in the production of T helper 2-type cytokines by Sap-deficient CD4+ T cells.

  • Impaired natural killer (NK)-cell and T-cell functions in patients with XLP seems to be caused by the sum of the dysregulation of the individual SLAM-receptor-induced pathways.

  • The SAP-related proteins EAT2A and EAT2B are expressed by professional antigen-presenting cells, in which they are thought to control signal transduction initiated by SLAM-related receptors.

Abstract

SAP (signalling lymphocytic activation molecule (SLAM)-associated protein) is a T- and natural killer (NK)-cell-specific protein containing a single SH2 domain encoded by a gene that is defective or absent in patients with X-linked lymphoproliferative syndrome (XLP). The SH2 domain of SAP binds with high affinity to the cytoplasmic tail of the haematopoietic cell-surface glycoprotein SLAM and five related receptors. SAP regulates signal transduction of the SLAM-family receptors by recruiting SRC kinases. Similarly, the SAP-related proteins EAT2A and EAT2B are thought to control signal transduction that is initiated by SLAM-related receptors in professional antigen-presenting cells. In this review, we discuss recent findings on the structure and function of proteins of the SAP and SLAM families.

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Figure 1: A model of the interaction between members of the SLAM family and the SAP- and EAT2-associated molecules at the interface of T cells and APCs.
Figure 2: Structure of SAP and location of missense mutations identified in patients with XLP.
Figure 3: Genomic organization of the SLAM-gene family.
Figure 4: A model of FYN activation and recruitment by SAP.

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Acknowledgements

We thank the members of the Engel, Eck and Terhorst laboratories for their valuable contributions to many of the studies reviewed here. We thank H. K. Song for preparing Figure 1. P.E. is supported by the Ministerio de Ciencia y Tecnología of Spain. C.T. and M.E. are supported by the National Institutes of Health.

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Correspondence to Pablo Engel.

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DATABASES

LocusLink

BLAME

CD244

CD48

CD84

CD84-H1

CD95

CRACC

EAT2

Eat2

FYN

IFN-γ

LAT

LY9

NTBA

PLC-γ

SAP

SHIP

SHP1

SHP2

SLAM

OMIM

CVID

XLP

Entrez

EBV

LCMV

Glossary

APLASTIC ANAEMIA

Anaemia produced by bone-marrow failure. It can be inherited or acquired. It might occur in the setting of viral infection.

VASCULITIS

Inflammation of the wall of blood vessels that might be accompanied by necrosis.

PULMONARY LYMPHOMATOID GRANULOMATOSIS

Consists of angiocentric immunoproliferative lesions that can progress to lymphomas. Most cases of lymphomatoid granulomatosis that involve the lung represent proliferating Epstein–Barr virus-infected B cells with a prominent T-cell reaction and vasculitis.

NON-HODGKIN LYMPHOMAS

Lymphocyte tumours that are derived from either T or B cells without the characteristics of Hodgkin disease.

HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

Histiocytic proliferation with marked haemophagocytosis usually associated with infection. It is particularly frequent in patients with fatal Epstein–Barr virus-induced infectious mononucleosis.

TWO-SIGNAL HYPOTHESIS

This hypothesis postulates that two signals are required for lymphocyte activation. The first signal is provided by the interaction of the antigen with the antigen-specific receptors and the second signal by co-stimulatory molecules.

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Engel, P., Eck, M. & Terhorst, C. The SAP and SLAM families in immune responses and X-linked lymphoproliferative disease. Nat Rev Immunol 3, 813–821 (2003). https://doi.org/10.1038/nri1202

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