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.

  • Correspondence
  • Published:

HVEM, a cosignaling molecular switch, and its interactions with BTLA, CD160 and LIGHT

Cellular & Molecular Immunology volume 16, pages 679–682 (2019)Cite this article

Subjects

Temporal and spatial expression of cosignaling receptors and their ligands regulates the early stages of T-cell activation (signal 1, T-cell receptor (TCR) signaling and signal 2, costimulation/coinhibition), clonal expansion and T-cell survival during their differentiation towards effector T cells. Once the inflammatory stimulus is eliminated, effector T cells return to homeostasis after undergoing a contraction phase by activation-induced cell death and the intervention of ligands for coinhibitory receptors, leaving a population of long-term memory T cells. The expression of ligands for coinhibitory receptors on hematopoietic cells and, more importantly, on non-hematopoietic cells of peripheral tissues is a key process in tuning the functional activity of effector T cells to prevent excess tissue inflammation that may lead to immunopathology and subsequent tissue dysfunction.

Two groups of proteins of the immunoglobulin superfamily (IgSF), CTLA-4/CD28/CD80/CD86 and PD-1/PD-L1/PD-L2, which function as cosignaling receptors and ligands, are the focus of intense research. The former group functions at the early phase of T-cell activation, and the latter group predominantly controls the effector phase of the immune response in peripheral tissues. In recent years, blockade of these immune checkpoints to potentiate effective antitumor responses has enormously advanced the field of cancer immunotherapy.1 However, only a subgroup of patients respond to therapy with current immune checkpoint inhibitors. Therefore, other modulators of the T-cell response need to be explored.

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

Relevant articles

Open Access articles citing this article.

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

Fig. 1

References

  1. van Elsas, A., Hurwitz, A. A. & Allison, J. P. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J. Exp. Med. 190, 355–366 (1999).

    Article  Google Scholar 

  2. Bossen, C. et al. Interactions of tumor necrosis factor (TNF) and TNF receptor family members in the mouse and human. J. Biol. Chem. 281, 13964–13971 (2006).

    Article  CAS  Google Scholar 

  3. Rodriguez-Barbosa, J. I., Fernandez-Renedo, C., Moral, A. M. B., Buhler, L. & Del Rio, M. L. T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway. Cell Mol. Immunol. 14, 497–510 (2017).

    Article  CAS  Google Scholar 

  4. 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 

  5. Bekiaris, V., Sedy, J. R., Macauley, M. G., Rhode-Kurnow, A. & Ware, C. F. The inhibitory receptor BTLA controls gammadelta T cell homeostasis and inflammatory responses. Immunity 39, 1082–1094 (2013).

    Article  CAS  Google Scholar 

  6. Jones, A. et al. Immunomodulatory functions of BTLA and HVEM govern induction of extrathymic regulatory T cells and tolerance by dendritic cells. Immunity 45, 1066–1077 (2016).

    Article  CAS  Google Scholar 

  7. Maeda, M. et al. Murine CD160, Ig-like receptor on NK cells and NKT cells, recognizes classical and nonclassical MHC class I and regulates NK cell activation. J. Immunol. 175, 4426–4432 (2005).

    Article  CAS  Google Scholar 

  8. Murphy, T. L. & Murphy, K. M. Slow down and survive: enigmatic immunoregulation by BTLA and HVEM. Annu. Rev. Immunol. 28, 389–411 (2010).

    Article  CAS  Google Scholar 

  9. Tu, T. C. et al. CD160 is essential for NK-mediated IFN-gamma production. J. Exp. Med. 212, 415–429 (2015).

    Article  CAS  Google Scholar 

  10. Hurchla, M. A., Sedy, J. R. & Murphy, K. M. Unexpected role of B and T lymphocyte attenuator in sustaining cell survival during chronic allostimulation. J. Immunol. 178, 6073–6082 (2007).

    Article  CAS  Google Scholar 

  11. Giles, D. A. et al. The tumor necrosis factor superfamily members TNFSF14 (LIGHT), lymphotoxin beta and lymphotoxin beta receptor interact to regulate intestinal inflammation. Front. Immunol. 9, 2585 (2018).

    Article  Google Scholar 

  12. Miller, M. L., Sun, Y. & Fu, Y. X. Cutting edge: B and T lymphocyte attenuator signalingon NKT cells inhibits cytokine release and tissue injuryin early immune responses. J. Immunol. 183, 32–36 (2009).

    Article  CAS  Google Scholar 

  13. Kim, T.J.P. et al. CD160 serves as a negative regulator of NKT cells in acute hepatic injury. Nat. Commun. (2019).

  14. Wang, Y. et al. The role of herpesvirus entry mediator as a negative regulator of T cell-mediated responses. J. Clin. Invest. 115, 711–717 (2005).

    Article  CAS  Google Scholar 

  15. Giustiniani, J., Marie-Cardine, A. & Bensussan, A. A soluble form of the MHC class I-specific CD160 receptor is released from human activated NK lymphocytes and inhibits cell-mediated cytotoxicity. J. Immunol. 178, 1293–1300 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grant FIS PI# 13/00029 (Fondo de Investigaciones Sanitarias, Ministry of Health, Spanish Government and cofunded by the European Union ERDF/ESF, “Investing in your future”), LE093U13 and Unit of Excellence Research UIC #012 (Department of Education of the Regional Government, Junta de Castilla y Leon) and Gerencia Regional de Salud (BIO/01/15), which were awarded to J.I.R.B. Miguel Servet National Grant (Health National Organization Research) CP12/03063, CPII17/00002 and FIS PI16/00002 (Instituto de Salud Carlos III and cofunded by European Union ERDF/ESF, “Investing in your future”), and Gerencia Regional de Salud GRS963/A/2014, GRS1142/A/2015 and GRS1505/A/2017 funded the research of M.L.R.G. The National Network CIBERONC (Oncology Research Program, referenced as CB16/12/00480) also cofunded this work. P.S. is funded by grant 31003A-176356 of the Swiss National Science Foundation. A.W. is funded by the grants Deutsche Krebshilfe (70112451) and Deutsche Forschungsgemeinschaft (SFB1039, and FOR2438).

Author contributions

We apologize to the authors of relevant contributions not included in the text due to restrictions of space and the numbers of quotes. J.I.R.B. wrote the manuscript with the main support of M.L.R. and P.S. The other coauthors contributed their expertise in the field to the reading of the manuscript, suggesting the general scheme and the topics to be addressed and providing essential input in regard to the general considerations and corrections.

Author information

Authors and Affiliations

  1. Transplantation Immunobiology Section, Research Institutes of the University of Leon, Campus of Vegazana s/n, 24071, Leon, Spain

    Jose Ignacio Rodriguez-Barbosa & Maria-Luisa del Rio

  2. Leon Regional Transplantation Coordination Center, Leon University Hospital, Leon, Spain

    Jose Ignacio Rodriguez-Barbosa & Maria-Luisa del Rio

  3. Acción Estratégica en Salud, Consorcio CIBER-ONC, Seville, Spain

    Jose Ignacio Rodriguez-Barbosa, Jose-Antonio Perez-Simon & Maria-Luisa del Rio

  4. Department of Biochemistry, University of Lausanne, 1066, Epalinges, Switzerland

    Pascal Schneider

  5. Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590, Frankfurt, Germany

    Andreas Weigert

  6. Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, 02841, Republic of Korea

    Kyung-Mi Lee & Tae-Jin Kim

  7. Department of Biomedical Engineering, Center for Bio-Integrated Electronics, Simpson Querrey Institute for BioNanotechnology, Northwestern University, Evanston, IL, 60208, USA

    Kyung-Mi Lee & Tae-Jin Kim

  8. Department of Hematology, Virgen del Rocio University Hospital, Biomedical Institute of Sevilla, Sevilla, Spain

    Jose-Antonio Perez-Simon

Authors
  1. Jose Ignacio Rodriguez-Barbosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pascal Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andreas Weigert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kyung-Mi Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tae-Jin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jose-Antonio Perez-Simon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maria-Luisa del Rio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jose Ignacio Rodriguez-Barbosa or Maria-Luisa del Rio.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rodriguez-Barbosa, J., Schneider, P., Weigert, A. et al. HVEM, a cosignaling molecular switch, and its interactions with BTLA, CD160 and LIGHT. Cell Mol Immunol 16, 679–682 (2019). https://doi.org/10.1038/s41423-019-0241-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-019-0241-1

This article is cited by

Search

Advanced search

Quick links