Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

SAP controls T cell responses to virus and terminal differentiation of TH2 cells

Nature Immunology volume 2, pages 410–414 (2001)Cite this article

Abstract

SH2D1A, which encodes signaling lymphocyte activation molecule (SLAM)–associated protein (SAP), is altered in patients with X-linked lymphoproliferative disease (XLP), a primary immunodeficiency. SAP-deficient mice infected with lymphocytic choriomeningitis virus had greatly increased numbers of CD8+ and CD4+ interferon-γ–producing spleen and liver cells compared to wild-type mice. The immune responses of SAP-deficient mice to infection with Leishmania major together with in vitro studies showed that activated SAP-deficient T cells had an impaired ability to differentiate into T helper 2 cells. The aberrant immune responses in SAP-deficient mice show that SAP controls several distinct key T cell signal transduction pathways, which explains in part the complexity of the XLP phenotypes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Targeted disruption of the gene encoding SAP, Sh2d1a.
Figure 2: Immune responses of SAP-deficient mice to LCMV infection.
Figure 3: Analysis of cytokine production in SAP-deficient T and NKT cells.
Figure 4: SAP-deficient mice are resistant to L. major infection.
Figure 5: Defective IgE production in SAP-deficient mice.

Similar content being viewed by others

References

  1. Sayos, J. et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395, 462–469 (1998).

    Article  CAS  Google Scholar 

  2. Coffey, A. J. et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nature Genet. 20, 129–135 (1998).

    Article  CAS  Google Scholar 

  3. Nichols, K. E. et al. Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proc. Natl Acad. Sci. USA 95, 13765–13770 (1998).

    Article  CAS  Google Scholar 

  4. Wu, C. et al. Genomic organization and characterization of mouse SAP, the gene that is altered in X-linked lymphoproliferative disease. Immunogenetics 51, 805–815 (2000).

    Article  CAS  Google Scholar 

  5. Parolini, S. et al. X-linked Lymphoproliferative Disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill epstein-barr virus-infected cells. J. Exp. Med. 192, 337–346 (2000).

    Article  CAS  Google Scholar 

  6. Tangye, S. G. et al. Cutting edge: human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP. J. Immunol. 162, 6981–6985 (1999).

    CAS  PubMed  Google Scholar 

  7. Benoit, L., Wang, X., Pabst, H.F., Dutz, J. & Tan, R. Defective natural killer cell activation in X-linked lymphoproliferative disease. J. Immunol. 165, 3549–3553 (2000).

    Article  CAS  Google Scholar 

  8. Sayos, J. et al. Potential pathways for regulation of NK and T cell responses: differential X-linked lymphoproliferative syndrome gene product SAP interactions with SLAM and 2B4. Int. Immunol. 12, 1749–1757 (2000).

    Article  CAS  Google Scholar 

  9. Sayos, J. et al. The cell surface receptors Ly-9 and CD84 recruit the XLP gene product SAP. Blood (in the press, 2001).

  10. Purtilo, D. T., Grierson, H. L., Davis, J. R. & Okano, M. The X-linked lymphoproliferative disease: from autopsy toward cloning the gene 1975–1990. Pediatr. Pathol. 11, 685–710 (1991).

    Article  CAS  Google Scholar 

  11. 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 

  12. Maia, D. M. & Garwacki, C. P. X-linked lymphoproliferative disease: pathology and diagnosis. Pediatr. Dev. Pathol. 2, 72–77 (1999).

    Article  CAS  Google Scholar 

  13. Morra, M. et al. X-linked lymphoproliferation disease: a progressive immunodeficiency. Annu. Rev. Immunol. 19, 657–682 (2001).

    Article  CAS  Google Scholar 

  14. Zinkernagel, R. M. et al. T cell-mediated hepatitis in mice infected with lymphocytic choriomeningitis virus. Liver cell destruction by H-2 class I-restricted virus-specific cytotoxic T cells as a physiological correlate of the 51Cr-release assay? J. Exp. Med. 164, 1075–1092 (1986).

    Article  CAS  Google Scholar 

  15. McIntyre, K. W. & Welsh, R. M. Accumulation of natural killer and cytotoxic T large granular lymphocytes in the liver during virus infection. J. Exp. Med. 164, 1667–1681 (1986).

    Article  CAS  Google Scholar 

  16. Yoshimoto, T. & Paul, W. E. CD4pos, NK1.1pos T cells promptly produce interleukin 4 in response to in vivo challenge with anti-CD3. J. Exp. Med. 179, 1285–1295 (1994).

    Article  CAS  Google Scholar 

  17. Yoshimoto, T., Bendelac, A., Watson, C., Hu-Li, J. & Paul, W. E. Role of NK1.1+ T cells in a TH2 response and in immunoglobulin E production. Science 270, 1845–1847 (1995).

    Article  CAS  Google Scholar 

  18. Yoshimoto, T., Bendelac, A., Hu-Li, J. & Paul, W. E. Defective IgE production by SJL mice is linked to the absence of CD4+, NK1.1+ T cells that promptly produce interleukin 4. Proc. Natl Acad. Sci. USA 92, 11931–11934 (1995).

    Article  CAS  Google Scholar 

  19. Himmelrich, H., Parra-Lopez, C., Tacchini-Cottier, F., Louis, J. A. & Launois, P. The IL-4 rapidly produced in BALB/c mice after infection with Leishmania major down-regulates IL-12 receptor β2-chain expression on CD4+ T cells resulting in a state of unresponsiveness to IL-12. J. Immunol. 161, 6156–6163 (1998).

    CAS  PubMed  Google Scholar 

  20. Launois, P. et al. IL-4 rapidly produced by Vβ 4Vα 8 CD4+ T cells instructs Th2 development and susceptibility to Leishmania major in BALB/c mice. Immunity 6, 541–549 (1997).

    Article  CAS  Google Scholar 

  21. Chatelain, R., Varkila, K. & Coffman, R. L. IL-4 induces a Th2 response in Leishmania major-infected mice. J. Immunol. 148, 1182–1187 (1992).

    CAS  PubMed  Google Scholar 

  22. Satoskar, A. R. et al. NK cell-deficient mice develop a Th1-like response but fail to mount an efficient antigen-specific IgG2a antibody response. J. Immunol. 163, 5298–5302 (1999).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Tangye, S. G., Phillips, J. H., Lanier, L. L. & Nichols, K. E. Functional requirement for SAP in 2B4-mediated activation of human natural killer cells as revealed by the X-linked lymphoproliferative syndrome. J. Immunol. 165, 2932–2936 (2000).

    Article  CAS  Google Scholar 

  25. Morra, M. et al. Missense mutations that affect non-phospho tyrosine interactions and stability of the SAP SH2-domain in X-linked proliferative disease patients. J. Exp. Med. (submitted, 2001).

  26. Cousens, L. P. et al. Two roads diverged: interferon α/β- and interleukin 12-mediated pathways in promoting T cell interferon γ responses during viral infection. J. Exp. Med. 189, 1315–1328 (1999).

    Article  CAS  Google Scholar 

  27. Murali-Krishna, K. et al. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 8, 177–187 (1998).

    Article  CAS  Google Scholar 

  28. Pien, G. C. & Biron, C. A. Compartmental differences in NK cell responsiveness to IL-12 during lymphocytic choriomeningitis virus infection. J. Immunol. 164, 994–1001 (2000).

    Article  CAS  Google Scholar 

  29. Satoskar, A. R. et al. Mice lacking NK cells develop an efficient TH1 response and control cutaneous Leishmania major infection. J. Immunol. 162, 6747–6754 (1999).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank L. Du and J. Burgess for their technical assistance in generating the SAP−/− mice; O. Leo, A. Bhan and S. Ju for their technical advice; J. Fingeroth, N. Houten and Y. Jong for a critical review of the manuscript and the NIAID Tetramer Facility, NIH AIDS Research and Reference Reagent Program and J. Altman for providing the LCMV tetramers. Supported by the Cancer Research Institute (C. W.), the Leukemia Society (D. H.) and grants from the NIH.

Author information

Authors and Affiliations

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

    Chengbin Wu, Ninghai Wang, Charles Gullo, Duncan Howie & Cox Terhorst

  2. Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, 02912, RI, USA

    Khuong B. Nguyen, Gary C. Pien & Christine A. Biron

  3. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, 02115, MA, USA

    Miriam Rodriguez Sosa & Abhay R. Satoskar

  4. Edward Jenner Institute for Vaccine Research, Compton, Newbury, RG20 7NN, Berkshire, UK

    Matthew J. Edwards & Persephone Borrow

  5. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, MA, USA

    Arlene H. Sharpe

Authors
  1. Chengbin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Khuong B. Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gary C. Pien
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ninghai Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Charles Gullo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Duncan Howie
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Miriam Rodriguez Sosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Matthew J. Edwards
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Persephone Borrow
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Abhay R. Satoskar
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Arlene H. Sharpe
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Christine A. Biron
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Cox Terhorst
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cox Terhorst.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, C., Nguyen, K., Pien, G. et al. SAP controls T cell responses to virus and terminal differentiation of TH2 cells. Nat Immunol 2, 410–414 (2001). https://doi.org/10.1038/87713

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/87713

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing