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The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM

Nature volume 395, pages 462–469 (1998)Cite this article

Abstract

In addition to triggering the activation of B- or T-cell antigen receptors, the binding of a ligand to its receptor at the cell surface can sometimes determine the physiological outcome of interactions between antigen-presenting cells, T and B lymphocytes. The protein SLAM (also known as CDw150), which is present on the surface of B and T cells, forms such a receptor–ligand pair as it is a self-ligand. We now show that a T-cell-specific, SLAM-associated protein (SAP), which contains an SH2 domain and a short tail, acts as an inhibitor by blocking recruitment of the SH2-domain-containing signal-transduction molecule SHP-2 to a docking site in the SLAM cytoplasmic region. The gene encoding SAP maps to the same area of the X chromosome as the locus for X-linked lymphoproliferative disease (XLP) and we found mutations in the SAP gene in three XLP patients. Absence of the inhibitor SAP in XLP patients affects T/B-cell interactions induced by SLAM, leading to an inability to control B-cell proliferation caused by Epstein–Barr virus infections.

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Figure 1: Comparison of deduced amino-acid sequences of human SAP, murine SAP and other SH2-domain-containing proteins.
Figure 2: Characterization of the human and murine SAP proteins and their interactions with SLAM.
Figure 3: SAP expression.
Figure 4: mRNA analysis of XLP patients.
Figure 5: Nucleotide and amino-acid sequences of SAP isolated from a patient with XLP.
Figure 6: Genomic analysis of patients with XLP.
Figure 7: The SAP SH2 domain binds to a specific sequence in the cytoplasmic domain of SLAM.
Figure 8: SAP blocks recruitment of the tyrosine phosphatase SHP-2 to the phosphorylated cytoplasmic domain of SLAM.
Figure 9: SAP has a positive effect in the SLAM co-stimulatory pathway.

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References

  1. Cocks, B. G. et al. Anovel receptor involved in T-cell activation. Nature 376, 260–263 (1995).

    Article  ADS  CAS  Google Scholar 

  2. Aversa, G. et al. SLAM and its role in T cell activation and Th cell responses. Immunol. Cell Biol. 75, 202–205 (1997).

    Article  CAS  Google Scholar 

  3. Aversa, G., Chang, C. J., Carballido, J. M., Cocks, B. G. & de Vries, J. E. Engagement of the signalling lymphocytic activation molecule (SLAM) on activated T cells results in IL-2-independent, cyclosporin A-sensitive T cell proliferation and IFN-gamma production. J. Immunol. 158, 4036–4044 (1997).

    CAS  PubMed  Google Scholar 

  4. Carballido, J. M. et al. Reversal of human allergic T helper 2 responses by engagement of signaling lymphocytic activation molecule. J. Immunol. 159, 4316–4321 (1997).

    CAS  PubMed  Google Scholar 

  5. Isomaki, P. et al. Increased expression of signaling lymphocytic activation molecule in patients with rheumatoid arthritis and its role in the regulation of cytokine production in rheumatoid synovium. J. Immunol. 159, 2986–2993 (1997).

    CAS  PubMed  Google Scholar 

  6. Punnonen, J. et al. Soluble and membrane-bound forms of signaling lymphocytic activation molecule (SLAM) induce proliferation and Ig synthesis by activated human B lymphocytes. J. Exp. Med. 185, 993–1004 (1997).

    Article  CAS  Google Scholar 

  7. Ferrante, P. et al. Cytokine production and surface marker expression in acute and stable multiple sclerosis: altered IL-12 production and augmented signaling lymphocytic activation molecule (SLAM)-expressing lymphocytes in acute multiple sclerosis. J. Immunol. 160, 1514–1521 (1998).

    CAS  PubMed  Google Scholar 

  8. Lamartine, J. et al. Physical map and cosmid contig encompassing a new interstitial deletion of the X-linked lymphoproliferative syndrome region. Eur. J. Hum. Genet. 4, 342–351 (1996).

    Article  CAS  Google Scholar 

  9. Porta, G. 4.5-Mb YAC STS contig 50-kb resolution, spanning Xq25 deletions in two patients with lymphoproliferative syndrome. Genome Res. 7, 27–36 (1997).

    Article  CAS  Google Scholar 

  10. Lanyi, A. et al. Ayeast artificial chromosome (YAC) contig encompassing the critical region of the X-linked lymphoproliferative disease (XLP) locus. Genomics 39, 55–56 (1997).

    Article  CAS  Google Scholar 

  11. Purtilo, D. T. Immunopathology of X-linked lymphoproliferative syndrome. Immunol. Today 4, 291–295 (1983).

    Article  CAS  Google Scholar 

  12. Seemayer, T. A. et al. X-linked lymphoproliferative disease: twenty-five years after the discovery. Pediatr. Res. 38, 471–478 (1995).

    Article  CAS  Google Scholar 

  13. Rousset, F., Souillet, G., Roncarolo, M. G. & Lamelin, J.-P. Studies of EBV-lymphoid cell interactions with the X-linked lymphoproliferative syndrome: normal EBV-specific HLA-restricted cytotoxicity. Clin. Exp. Immunol. 63, 280–289 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Cooper, D. M. & Krawczak, M. Human Gene Mutations (Bios Scientific, Oxford, (1993)).

    Google Scholar 

  15. Marengere, L. E. et al. Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4. Science 272, 1170–1173 (1996).

    Article  ADS  CAS  Google Scholar 

  16. Sutkowski, N. et al. An Epstein-Barr virus-associated superantigen. J. Exp. Med. 184, 971–800 (1996).

    Article  CAS  Google Scholar 

  17. Ridge, J. P., Di Rosa, F. & Matzinger, P. Aconditioned dendritic cell can be a temporal bridge between a CDR+ T-helper and a T-killer cell. Nature 393, 474–478 (1998).

    Article  ADS  CAS  Google Scholar 

  18. Schoenberger, S. P., Toes, R. E. M., van der Voort, E. I. H., Offringa, R. & Melief, C. J. M. T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions. Nature 393, 480–483 (1998).

    Article  ADS  CAS  Google Scholar 

  19. Bennett, S. R. M. et al. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393, 478–480 (1998).

    Article  ADS  CAS  Google Scholar 

  20. Ramesh, N., Anton, I. M., Hartwig, J. H. & Geha, R. S. WIP, a protein associated with Wiskott-Aldrich syndrome protein, induces actin polymerization and redistribution in lymphoid cells. Proc. Natl Acad. Sci. USA 94, 14671–14676 (1997).

    Article  ADS  CAS  Google Scholar 

  21. Wang, B. et al. Over-expression of CD3-ε transgenes blocks T lymphocyte development. Intl. Immunol. 7, 435–448 (1995).

    Article  CAS  Google Scholar 

  22. de Aos, I. et al. Tyrosine phosphorylation of the CD3-epsilon subunit of the T cell antigen receptor mediates enhanced association with phosphatidylinositol 3-kinase in Jurkat cells. J. Biol. Chem. 40, 25310–25318 (1997).

    Article  Google Scholar 

  23. Martinez-Martinez, S. et al. Blockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells. Mol. Cell. Biol. 17, 6437–6447 (1997).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank J. David, J. Fingeroth and N. Letvin for critically reviewing the manuscript; J. Sumegi for sharing unpublished data; N. van Orsouw and J. Vijg for guidance in analysing PCR products; and E. Wang, M. Comiskey, A. Bywater and A. Hren for technical assistance. This work was supported by a grant from the NIH. J.S. is supported by a fellowship from the Ministerio de Educacion y Cultura de España.

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Authors and Affiliations

  1. Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, Massachusetts, USA

    J. Sayos, C. Wu, M. Morra, N. Wang, X. Zhang, D. Allen, S. van Schaik & C. Terhorst

  2. Department of Pediatrics, University of Brescia, Brescia, 25125, Italy

    L. Notarangelo

  3. Division of Immunology, The Children's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    R. Geha & H. Oettgen

  4. Cellular Therapy Laboratory, Telethon Institute for Gene Therapy, Milan, 20132, Italy

    M. G. Roncarolo

  5. Novartis Forschungsinstitut Geselschaft mbH, Vienna, A-1235, Austria

    J. E. De Vries & G. Aversa

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  1. J. Sayos
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Correspondence to J. Sayos or C. Terhorst.

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Sayos, J., Wu, C., Morra, M. et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395, 462–469 (1998). https://doi.org/10.1038/26683

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