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:

B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator

Nature Immunology volume 6, pages 90–98 (2005)Cite this article

Abstract

B and T lymphocyte attenuator (BTLA) provides an inhibitory signal to B and T cells. Previously, indirect observations suggested that B7x was a ligand for BTLA. Here we show that BTLA does not bind B7x; instead, we identify herpesvirus entry mediator (HVEM) as the unique BTLA ligand. BTLA bound the most membrane-distal cysteine-rich domain of HVEM, distinct from regions where the ligands LIGHT and lymphotoxin-α bound HVEM. HVEM induced BTLA tyrosine phosphorylation and association of the tyrosine phosphatase SHP-2 and repressed antigen-driven T cell proliferation, providing an example of reverse signaling to a non–tumor necrosis factor family ligand. The conservation of the BTLA-HVEM interaction between mouse and human suggests that this system is an important pathway regulating lymphocyte activation and/or homeostasis in the immune response.

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: BTLA recognizes a ligand on naive T cells.
Figure 2: BTLA tetramer staining identifies a ligand on CD4+ and CD8+ cells.
Figure 3: BTLA ligand expression is modulated during T cell activation.
Figure 4: HVEM is a ligand for BTLA.
Figure 5: HVEM is the unique ligand for BTLA and interacts through CRD1.
Figure 6: HVEM expression on APCs inhibits T cell proliferation.
Figure 7: HVEM inhibits T cell proliferation in a BTLA-dependent way.

Similar content being viewed by others

References

  1. Watanabe, N. et al. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nat. Immunol. 4, 670–679 (2003).

    Article  CAS  Google Scholar 

  2. Han, P. et al. An inhibitory Ig superfamily protein expressed by lymphocytes and APCs is also an early marker of thymocyte positive selection. J. Immunol. 172, 5931–5939 (2004).

    Article  CAS  Google Scholar 

  3. Gavrieli, M. et al. Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of B and T lymphocyte attenuator required for association with protein tyrosine phosphatases SHP-1 and SHP-2. Biochem. Biophys. Res. Commun. 312, 1236–1243 (2003).

    Article  CAS  Google Scholar 

  4. Suzuki, Y. et al. HAX-1, a novel intracellular protein, localized on mitochondria, directly associates with HS1, a substrate of Src family tyrosine kinases. J. Immunol. 158, 2736–2744 (1997).

    CAS  PubMed  Google Scholar 

  5. Prasad, D.V. et al. B7S1, a novel B7 family member that negatively regulates T cell activation. Immunity 18, 863–873 (2003).

    Article  CAS  Google Scholar 

  6. Sica, G.L. et al. B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity 18, 849–861 (2003).

    Article  CAS  Google Scholar 

  7. Zang, X. et al. B7x: a widely expressed B7 family member that inhibits T cell activation. Proc. Natl. Acad. Sci. USA 100, 10388–10392 (2003).

    Article  CAS  Google Scholar 

  8. Agata, Y. et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 8, 765–772 (1996).

    Article  CAS  Google Scholar 

  9. Croft, M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat. Rev. Immunol. 3, 609–620 (2003).

    Article  CAS  Google Scholar 

  10. Mauri, D.N. et al. LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity 8, 21–30 (1998).

    Article  CAS  Google Scholar 

  11. Tamada, K. et al. LIGHT, a TNF-like molecule, costimulates T cell proliferation and is required for dendritic cell-mediated allogeneic T cell response. J. Immunol. 164, 4105–4110 (2000).

    Article  CAS  Google Scholar 

  12. Morel, Y. et al. The TNF superfamily members LIGHT and CD154 (CD40 ligand) costimulate induction of dendritic cell maturation and elicit specific CTL activity. J. Immunol. 167, 2479–2486 (2001).

    Article  CAS  Google Scholar 

  13. Morel, Y. et al. Reciprocal expression of the TNF family receptor herpes virus entry mediator and its ligand LIGHT on activated T cells: LIGHT down-regulates its own receptor. J. Immunol. 165, 4397–4404 (2000).

    Article  CAS  Google Scholar 

  14. Sarrias, M.R. et al. The three HveA receptor ligands, gD, LT-α and LIGHT bind to distinct sites on HveA. Mol. Immunol. 37, 665–673 (2000).

    Article  CAS  Google Scholar 

  15. Carfi, A. et al. Herpes simplex virus glycoprotein D bound to the human receptor HveA. Mol. Cell 8, 169–179 (2001).

    Article  CAS  Google Scholar 

  16. Kwon, B.S. et al. A newly identified member of the tumor necrosis factor receptor superfamily with a wide tissue distribution and involvement in lymphocyte activation. J. Biol. Chem. 272, 14272–14276 (1997).

    Article  CAS  Google Scholar 

  17. Jung, H.W. et al. High levels of soluble herpes virus entry mediator in sera of patients with allergic and autoimmune diseases. Exp. Mol. Med. 35, 501–508 (2003).

    Article  CAS  Google Scholar 

  18. Latchman, Y. et al. PD-L2 is a second ligand for PD-I and inhibits T cell activation. Nat. Immunol. 2, 261–268 (2001).

    Article  CAS  Google Scholar 

  19. Bodmer, J.L., Schneider, P. & Tschopp, J. The molecular architecture of the TNF superfamily. Trends Biochem. Sci. 27, 19–26 (2002).

    Article  CAS  Google Scholar 

  20. McDonald, N.Q. & Hendrickson, W.A. A structural superfamily of growth factors containing a cystine knot motif. Cell 73, 421–424 (1993).

    Article  CAS  Google Scholar 

  21. Kirchner, S. et al. LPS resistance in monocytic cells caused by reverse signaling through transmembrane TNF (mTNF) is mediated by the MAPK/ERK pathway. J. Leukoc. Biol. 75, 324–331 (2004).

    Article  CAS  Google Scholar 

  22. Wiley, S.R., Goodwin, R.G. & Smith, C.A. Reverse signaling via CD30 ligand. J. Immunol. 157, 3635–3639 (1996).

    CAS  PubMed  Google Scholar 

  23. Shi, G. et al. Mouse T cells receive costimulatory signals from LIGHT, a TNF family member. Blood 100, 3279–3286 (2002).

    Article  CAS  Google Scholar 

  24. Suzuki, I. & Fink, P.J. Maximal proliferation of cytotoxic T lymphocytes requires reverse signaling through Fas ligand. J. Exp. Med. 187, 123–128 (1998).

    Article  CAS  Google Scholar 

  25. Lee, K.M. et al. Molecular basis of T cell inactivation by CTLA-4. Science 282, 2263–2266 (1998).

    Article  CAS  Google Scholar 

  26. Granger, S.W. & Rickert, S. LIGHT-HVEM signaling and the regulation of T cell-mediated immunity. Cytokine Growth Factor Rev. 14, 289–296 (2003).

    Article  CAS  Google Scholar 

  27. Paust, S. et al. Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease. Proc. Natl. Acad. Sci. USA 101, 10398–10403 (2004).

    Article  CAS  Google Scholar 

  28. Taylor, P.A. et al. B7 expression on T cells down-regulates immune responses through CTLA-4 ligation via T-T interactions. J. Immunol. 172, 34–39 (2004).

    Article  CAS  Google Scholar 

  29. Murphy, K.M., Heimberger, A.B. & Loh, D.Y. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science 250, 1720–1723 (1990).

    Article  CAS  Google Scholar 

  30. Scheu, S. et al. Targeted disruption of LIGHT causes defects in costimulatory T cell activation and reveals cooperation with lymphotoxin β in mesenteric lymph node genesis. J. Exp. Med. 195, 1613–1624 (2002).

    Article  CAS  Google Scholar 

  31. Arthos, J. et al. Biochemical and biological characterization of a dodecameric CD4-Ig fusion protein: implications for therapeutic and vaccine strategies. J. Biol. Chem. 277, 11456–11464 (2002).

    Article  CAS  Google Scholar 

  32. Arase, H. et al. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296, 1323–1326 (2002).

    Article  CAS  Google Scholar 

  33. Lybarger, L. et al. Enhanced immune presentation of a single-chain major histocompatibility complex class I molecule engineered to optimize linkage of a C-terminally extended peptide. J. Biol. Chem. 278, 27105–27111 (2003).

    Article  CAS  Google Scholar 

  34. Ouyang, W. et al. Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. Immunity 12, 27–37 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Fremont, C. Nelson and O. Naidenko for help with tetramer production and for discussions, and V. Grigura and J.C. Walsh for technical assistance. Supported by the Howard Hughes Medical Institute (K.M.M.) and the National Institutes of Health (PO1 AI31238 and P50 HL54619 to K.M.M.; AI33068, CA69381 and AI48073 to C.F.W.; and AG00252 to K.P.).

Author information

Authors and Affiliations

  1. Department of Pathology and Center for Immunology, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    John R Sedy, Maya Gavrieli, Michelle A Hurchla, R Coleman Lindsley, Kai Hildner, Theresa L Murphy & Kenneth M Murphy

  2. Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, 92121, California, USA

    Karen G Potter & Carl F Ware

  3. Institute of Medical Microbiology, University of Düsseldorf, Düsseldorf, Germany

    Stefanie Scheu & Klaus Pfeffer

  4. Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Kenneth M Murphy

Authors
  1. John R Sedy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maya Gavrieli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Karen G Potter
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michelle A Hurchla
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R Coleman Lindsley
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kai Hildner
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stefanie Scheu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Klaus Pfeffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Carl F Ware
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Theresa L Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kenneth M Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenneth M Murphy.

Ethics declarations

Competing interests

Some of the authors have applied for a patent that concerns the BTLA-HVEM interaction and its uses.

Supplementary information

Supplementary Fig. 1

BTLA does not directly interact with B7x. (PDF 39 kb)

Supplementary Fig. 2

Sequences of HVEM isolated from retroviral library. (PDF 45 kb)

Supplementary Fig. 3

Expression of BTLA and HVEM by EL-4 cells. (PDF 26 kb)

Supplementary Fig. 4

Increased expression of HVEM by Btla−/− lymphocytes. (PDF 49 kb)

Supplementary Fig. 5

Expression of I-Ad, B7.1, BTLA and HVEM on CHO cells. (PDF 56 kb)

Supplementary Table 1

Oligonucleotide sequences used in plasmid construction. (PDF 11 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sedy, J., Gavrieli, M., Potter, K. et al. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol 6, 90–98 (2005). https://doi.org/10.1038/ni1144

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1144

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