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SLAM receptors and SAP influence lymphocyte interactions, development and function

Nature Reviews Immunology volume 9, pages 39–46 (2009)Cite this article

Key Points

  • Mutations that affect the adaptor molecule SLAM-associated protein (SAP) lead to the genetic disorder X-linked lymphoproliferative syndrome (XLP), which is characterized by severe, often fulminant infections with Epstein–Barr virus, lymphoproliferative disorders (including lymphomas) and dysgammaglobulinaemia that can progress to hypogammaglobulinaemia.

  • SAP is required for signalling downstream of members of the signalling lymphocytic activation molecule (SLAM) family of immunomodulatory receptors.

  • Examination of humoral responses in SAP-deficient mice has shown impaired germinal-centre formation and severely reduced numbers of long-lived plasma cells and memory B cells. Similar findings have now been confirmed in humans with XLP.

  • New findings from in vivo intravital imaging have revealed that SAP-deficient CD4+ T cells show normal adhesion to and activation by dendritic cells but impaired adhesion to activated B cells. These findings suggest that SAP-deficient CD4+ T cells cannot deliver contact-dependent signals that are required for B-cell proliferation and germinal-centre formation, providing new insights into the defects associated with SAP deficiency.

  • SAP is also required in mice for the development of natural killer T (NKT) cells and other innate T-cell lineages that are selected by haematopoietic cells in the thymus (specifically, innate T-cell populations that are selected by double-positive thymocytes). A lack of NKT cells has also been confirmed in patients with XLP. Whether and how these effects on innate T-cell lineages affect the phenotypes of XLP are not clear, but patients with a variant of XLP that is caused by mutations that affect a different gene also lack NKT cells.

  • These findings suggest that SAP and SLAM family members affect the lymphocyte interactions that are required for development and differentiation, and raise the question of how defective lymphocyte–lymphocyte adhesion contributes to phenotypes that are associated with XLP.

Abstract

Mutations that affect the adaptor molecule SLAM-associated protein (SAP) underlie the primary immunodeficiency disease X-linked lymphoproliferative syndrome. SAP is required for mediating signals from members of the signalling lymphocytic activation molecule (SLAM) family of immunomodulatory receptors. Recent data have highlighted a role for SAP in the development of innate-like T-cell lineages, including natural killer T cells, and in the regulation of the interactions between B cells and T cells that are required for germinal-centre formation and long-term humoral immunity. These data have revealed that SLAM family members and SAP have crucial roles in regulating lymphocyte interactions and adhesion, which are required for the normal development, homeostasis and function of the immune system.

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Figure 1: Signal transduction by signalling lymphocytic activation molecule family members.
Figure 2: Pathways that regulate conventional and innate-like T-cell development in the thymus.
Figure 3: Events leading to the formation of germinal centres in vivo.
Figure 4: SLAM-associated protein specifically affects T-cell–B-cell interactions.

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Acknowledgements

We acknowledge the contributions of the many investigators in the field and of the patients with XLP, and apologize to those that we could not cite owing to space limitations.

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Authors and Affiliations

  1. National Human Genome Research Institute, Bethesda, 20892, Maryland, USA

    Pamela L. Schwartzberg, Kristen L. Mueller & Jennifer L. Cannons

  2. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Hai Qi

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  1. Pamela L. Schwartzberg
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  2. Kristen L. Mueller
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  4. Jennifer L. Cannons
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Corresponding author

Correspondence to Pamela L. Schwartzberg.

Supplementary information

Supplementary Information, Movie 1

Sap−/− T cells form short-lived conjugates. An example of distinct interactions of Sap+/+ (green) and Sap−/− (red) T cells with wild-type antigen-presenting B cells (blue) in vivo. See lower right for a long-lasting interaction between a Sap+/+ T cell and wild-type B cell; upper left for a short-lived interaction between a Sap−/− T cell and wild-type B cell. (MOV 1981 kb)

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Glossary

SH2 domain

A protein domain that is commonly found in signal-transduction molecules. An SH2 domain interacts specifically with phosphotyrosine-containing peptides.

Germinal centre

A lymphoid structure that arises within follicles following immunization with, or exposure to, a T-cell-dependent antigen. The germinal centre is specialized for facilitating the development of high-affinity, long-lived plasma cells and memory B cells.

Systemic lupus erythematosus

(SLE). An autoimmune disease in which autoantibodies that are specific for DNA, RNA or proteins associated with nucleic acids form immune complexes that damage small blood vessels, especially in the kidneys. Patients with SLE generally have abnormal B-cell and T-cell function.

Immunological synapse

A large junctional structure that is formed at the cell surface between a T cell and an antigen-presenting cell (APC) and consists of molecules that are required for adhesion and signalling. This structure is important in establishing T-cell adhesion and polarity, is influenced by the cytoskeleton and transduces highly controlled secretory signals, thereby allowing the directed release of cytokines or lytic granules towards the APC or target cell.

Positive selection

The process in the thymus that selects thymocytes expressing T-cell receptors (TCRs) that can interact weakly with self MHC molecules. This weak interaction generates differentiation and survival signals in these lymphocytes, the TCRs of which later recognize foreign peptides bound to self MHC. Positive selection establishes the MHC-restricted T-cell repertoire.

TEC family kinase

An enzyme that belongs to a family of non-receptor protein tyrosine kinases that contain a pleckstrin-homology domain. The prototype members are ITK (IL-2-inducible T-cell kinase) in T cells and BTK (Bruton's tyrosine kinase) in B cells. TEC-family kinases are involved in the intracellular signalling mechanisms of cytokine receptors, lymphocyte antigen receptors, heterotrimeric G-protein-coupled receptors and integrins.

T-cell-dependent antigen

A protein antigen that needs to be recognized by T helper cells (in the context of MHC molecules) and requires cooperation between these antigen-specific T cells and B cells for a specific antibody response to be generated.

Plasma cells

A non-dividing, terminally differentiated, immunoglobulin-secreting cell of the B-cell lineage.

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Schwartzberg, P., Mueller, K., Qi, H. et al. SLAM receptors and SAP influence lymphocyte interactions, development and function. Nat Rev Immunol 9, 39–46 (2009). https://doi.org/10.1038/nri2456

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