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.

  • Letter
  • Published:

Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors

Nature volume 413, pages 420–425 (2001)Cite this article

Abstract

Many pathological processes, including those causing allergies and autoimmune diseases, are associated with the presence of specialized subsets of T helper cells (TH1 and TH2) at the site of inflammation1,2,3,4. The diversity of TH1 and TH2 function is not predetermined but depends on signals that drive the cells towards either subset1,2,3,4. Histamine, released from effector cells (mast cells and basophils) during inflammatory reactions can influence immune response5,6,7,8. Here we report that histamine enhances TH1-type responses by triggering the histamine receptor type 1 (H1R), whereas both TH1- and TH2-type responses are negatively regulated by H2R through the activation of different biochemical intracellular signals. In mice, deletion of H1R results in suppression of interferon (IFN)-γ and dominant secretion of TH2 cytokines (interleukin (IL)-4 and IL-13). Mutant mice lacking H2R showed upregulation of both TH1 and TH2 cytokines. Relevant to T-cell cytokine profiles, mice lacking H1R displayed increased specific antibody response with increased immunoglobulin-ε (IgE) and IgG1, IgG2b and IgG3 compared with mice lacking H2R. These findings account for an important regulatory mechanism in the control of inflammatory functions through effector-cell-derived histamine.

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: Histamine receptor expression on TH1 and TH2 cells.
Figure 2: Histamine-induced intracellular calcium [Ca2+]i flux and cAMP in TH1 and TH2 cells.
Figure 3: Regulation of TH1- and TH2-type responses by histamine.
Figure 4: T-cell cytokine profiles in wild-type (WT), H1R-deleted and H2R-deleted mice.
Figure 5: OVA-specific immunoglobulin production in wild-type (WT), H1R-deleted and H2R-deleted mice.

Similar content being viewed by others

References

  1. Abbas, A. K., Murphy, K. M. & Sher, A. Functional diversity of helper T lymphocytes. Nature 383, 787–793 (1996).

    Article  ADS  CAS  Google Scholar 

  2. Chen, Q. et al. Development of Th1-type immune responses requires the type 1 cytokine receptor TCCR. Nature 407, 916–920 (2000).

    Article  ADS  CAS  Google Scholar 

  3. Sallusto, F., Mackay, C. R. & Lanzavecchia, A. Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells. Science 277, 2005–2007 (1997).

    Article  CAS  Google Scholar 

  4. Mosmann, T. R., Cherwinski, H., Bond, M. W., Giedlin, M. A. & Coffman, R. L. Two types of murine helper T cell clones. 1. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136, 2348–2357 (1986).

    CAS  PubMed  Google Scholar 

  5. Roszkowski, W., Plaut, M. & Lichtenstein, L. M. Selective display of histamine receptors on lymphocytes. Science 195, 683–685 (1977).

    Article  ADS  CAS  Google Scholar 

  6. Beer, D. J. & Rocklin, R. E. Histamine modulation of lymphocyte biology: Membrane receptors, signal transduction, and functions. Crit. Rev. Immunol. 7, 55–91 (1987).

    CAS  PubMed  Google Scholar 

  7. Vannier, E. & Dinarello, C. Histamine enhances interleukin (IL)-1-induced IL-1 gene expression and protein synthesis via H2 receptors in peripheral blood mononuclear cells. Comparison with IL-1 receptor antagonist. J. Clin. Invest. 92, 281–287 (1993).

    Article  CAS  Google Scholar 

  8. Banu, Y. & Watanabe, T. Augmentation of antigen receptor-mediated responses by histamine H1 receptor signaling. J. Exp. Med. 189, 673–682 (1999).

    Article  CAS  Google Scholar 

  9. Yamashita, M. et al. Expression cloning of a cDNA encoding the bovine histamine H1 receptor. Proc. Natl Acad. Sci. USA 88, 11515–11519 (1991).

    Article  ADS  CAS  Google Scholar 

  10. Gantz, I. et al. Molecular basis for the interaction of histamine with the histamine H2 receptor. J. Biol. Chem. 267, 20840–20843 (1992).

    CAS  PubMed  Google Scholar 

  11. Leurs, R., Smit, M. J. & Timmerman, H. Molecular pharmacological aspects of histamine receptors. Pharmacol. Ther. 66, 413–463 (1995).

    Article  CAS  Google Scholar 

  12. Boss, V., Talpade, D. J. & Murphy, T. J. Induction of NFAT-mediated transcription by Gq-coupled receptors in lymphoid and non-lymphoid cells. J. Biol. Chem. 271, 10429–10432 (1996).

    Article  CAS  Google Scholar 

  13. Plaut, M., Marone, G. & Gillespie, E. The role of cyclic AMP in modulating cytotoxic T lymphocytes. II. Sequential changes during culture in responsiveness of cytotoxic lymphocytes to cyclic AMP-active agents. J. Immunol. 131, 2945–2952 (1983).

    CAS  PubMed  Google Scholar 

  14. Novak, T. J. & Rothenberg, E. V. cAMP inhibits induction of interleukin 2 but not of interleukin 4 in T cells. Proc. Natl Acad. Sci. USA 87, 9353–9357 (1990).

    Article  ADS  CAS  Google Scholar 

  15. Bodor, J., Spetz, A., Strominger, J. L. & Habener, J. F. cAMP inducibility of transcriptional repressor ICER in developing and mature T lymphocytes. Proc. Natl Acad. Sci. USA 93, 3536–3541 (1996).

    Article  ADS  CAS  Google Scholar 

  16. Del Prete, G. F., De Carli, M. & Mastromauro, C. Purified protein derivate of Mycobacterium tuberculosis and excretory-secretory antigen(s) of Toxocara canis expand in vitro human T cells with stable and opposite (type 1 T helper or type 2 T helper) profiles of cytokine production. J. Clin. Invest. 88, 344–350 (1991).

    Article  Google Scholar 

  17. Robinson, D. S. et al. Predominant Th2-like bronchoalveolar T lymphocyte population in atopic asthma. N. Engl. J. Med. 326, 298–304 (1992).

    Article  CAS  Google Scholar 

  18. Akdis, C. A., Joss, A., Akdis, M., Faith, A. & Blaser, K. A molecular basis for T cell suppression by IL-10: CD28-associated IL-10 receptor inhibits CD28 tyrosine phosphorylation and phosphatidylinositol 3-kinase binding. FASEB J. 14, 1666–1668 (2000).

    Article  CAS  Google Scholar 

  19. Inoue, I. et al. Impaired locomotor activity and exploratory behaviour in mice lacking histamine H1 receptors. Proc. Natl Acad. Sci. USA 93, 13316–13320 (1996).

    Article  ADS  CAS  Google Scholar 

  20. Kobayashi, T. et al. Abnormal function and morphological regulation of the gastric mucosa in histamine H2 receptor-deficient mice. J. Clin. Invest. 105, 1741–1749 (2000).

    Article  CAS  Google Scholar 

  21. Mobarakeh, I. J. et al. Role of histamine H(1) receptor in pain perception: a study of the receptor gene knockout mice. Eur. J. Pharmacol. 391, 81–89 (2000).

    Article  CAS  Google Scholar 

  22. Corry, D. B. & Kheradmand, F. Induction and regulation of the IgE response. Nature 402, B18–B23 (1999).

    Article  ADS  CAS  Google Scholar 

  23. Akdis, C. A. & Blaser, K. IL-10 induced peripheral T cell anergy and reactivation by microenvironmental cytokines: two key steps in specific immunotherapy. FASEB J. 13, 603–609 (1999).

    Article  CAS  Google Scholar 

  24. Jutel, M. et al. Influence of bee venom immunotherapy on degranulation and leukotriene generation in human blood basophils. Clin. Exp. Allergy 26, 1112–1118 (1996).

    Article  CAS  Google Scholar 

  25. Lantz, C. S. et al. Role for interleukin-3 in mast-cell and basophil development and in immunity to parasites. Nature 392, 90–93 (1998).

    Article  ADS  CAS  Google Scholar 

  26. Akdis, C. A., Blesken, T., Akdis, M., Wuthrich, B. & Blaser, K. The role of IL-10 in specific immunotherapy. J. Clin. Invest. 102, 98–106 (1998).

    Article  CAS  Google Scholar 

  27. Jutel, M. et al. Bee venom immunotherapy results in decrease of IL-4 and IL-5 and increase of IFN-γ secretion in specific allergen-stimulated T-cell cultures. J. Immunol. 154, 4187–4194 (1995).

    CAS  PubMed  Google Scholar 

  28. Faith, A., Akdis, C. A., Akdis, M., Simon, H. U. & Blaser, K. Defective TCR stimulation in anergized Th2 cells correlates with abrogated p56lck and ZAP70 tyrozine kinase activities. J. Immunol. 159, 53–60 (1997).

    CAS  PubMed  Google Scholar 

  29. Watanabe, N., Katakura, K., Kobayashi, A., Okumura, K. & Ovary, Z. Protective immunity and eosinoiphilia in IgE-deficient SJA/9 mice infected with Nippostrongylus brasiliensis and Trishinella spiralis. Proc. Natl Acad. Sci. USA 85, 4460–4462 (1988).

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. M. Zinkernagel, F. Melchers and J. E. DeVries for critically reviewing the manuscript, as well as C. H. Heusser and S. Alkan for anti-IL-4 and anti-IFN-γ antibodies. This work was sponsored by the Swiss National Science Foundation.

Author information

Authors and Affiliations

  1. Swiss Institute of Allergy and Asthma Research (SIAF), Obere Strasse 22, Davos, CH-7270, Switzerland

    Marek Jutel, Sven Klunker, Mübeccel Akdis, Olivier A. R. Thomet, Kurt Blaser & Cezmi A. Akdis

  2. Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan

    Takeshi Watanabe, Ritsuko Koga & Takashi Kobayashi

  3. Department of Internal Medicine and Allergology, Wroclaw Medical University, Traugutta 57, Wroclaw, 50-417, Poland

    Jozef Malolepszy & Teresa Zak-Nejmark

Authors
  1. Marek Jutel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takeshi Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sven Klunker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mübeccel Akdis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Olivier A. R. Thomet
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jozef Malolepszy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Teresa Zak-Nejmark
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ritsuko Koga
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takashi Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kurt Blaser
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Cezmi A. Akdis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Marek Jutel or Cezmi A. Akdis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jutel, M., Watanabe, T., Klunker, S. et al. Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature 413, 420–425 (2001). https://doi.org/10.1038/35096564

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35096564

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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