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:

ICOS is essential for effective T-helper-cell responses

Abstract

The outcome of T-cell responses after T-cell encounter with specific antigens is modulated by co-stimulatory signals, which are required for both lymphocyte activation and development of adaptive immunity1,2,3. ICOS4,5, an inducible co-stimulator with homology to CD28, is expressed on activated, but not resting T cells, and shows T-cell co-stimulatory function in vitro. ICOS binds specifically to its counter-receptor B7RP-1 (refs 5,6,7), but not to B7-1 or B7-2. Here we provide in vivo genetic evidence that ICOS delivers a co-stimulatory signal that is essential both for efficient interaction between T and B cells and for normal antibody responses to T-cell-dependent antigens. To determine the physiological function of ICOS, we generated and characterized gene-targeted ICOS-deficient mice. In vivo, a lack of ICOS results in severely deficient T-cell-dependent B-cell responses. Germinal centre formation is impaired and immunoglobulin class switching, including production of allergy-mediating IgE, is defective. ICOS-deficient T cells primed in in vivo and restimulated in vitro with specific antigen produce only low levels of interleukin-4, but remain fully competent to produce interferon-γ.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Generation of ICOS-deficient mice.
Figure 2: Reduced basal IgG1 levels in ICOS-/- mice.
Figure 3: Impaired primary antibody responses and germinal centre formation in ICOS-/- mice challenged with T-cell-dependent antigens.
Figure 4: Impaired secondary antibody responses to T-cell-dependent antigens but normal responses to T-independent antigens in ICOS-/- mice.

Similar content being viewed by others

References

  1. McAdam, A. J., Schweitzer, A. N. & Sharpe, A. H. The role of B7 co-stimulation in activation and differentiation of CD4+ and CD8+ T cells. Immunol. Rev. 165, 231–247 ( 1998).

    Article  CAS  Google Scholar 

  2. Lenschow, D. J., Walunas, T. L. & Bluestone, J. A. CD28/B7 system of T cell costimulation. Annu. Rev. Immunol. 14, 233–258 (1996).

    Article  CAS  Google Scholar 

  3. Watts, T. H. & DeBenedette, M. A. T cell co-stimulatory molecules other than CD28. Cur. Opin. Immunol. 11, 286–293 (1999).

    Article  CAS  Google Scholar 

  4. Hutloff, A. et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397, 263–266 (1999).

    Article  ADS  CAS  Google Scholar 

  5. Yoshinaga, S. K. et al. T-cell co-stimulation through B7RP-1 and ICOS. Nature 402, 827–832 ( 1999).

    Article  ADS  CAS  Google Scholar 

  6. Swallow, M. M., Wallin, J. J. & Sha, W. C. B7h, a novel costimulatory homolog of B7.1 and B7.2, is induced by TNFα. Immunity 11, 423 –432 (1999).

    Article  CAS  Google Scholar 

  7. Aicher, A. et al. Characterization of human inducible costimulator ligand expression and function. J. Immunol. 164, 4689 –4696 (2000).

    Article  CAS  Google Scholar 

  8. Coyle, A. J. et al. The CD28-related molecule ICOS is required for effective T cell-dependent immune responses. Immunity 13, 95–105 (2000).

    Article  CAS  Google Scholar 

  9. Statistical Methods in the Pharmaceutical Industry 2nd edn (eds Buncher, C. R. & Tsay, J.-Y.) 517– 518 (Marcel Dekker, New York, 1994).

  10. Grusby, M. J. & Glimcher, L. H. Immune responses in MHC class II-deficient mice. Annu. Rev. Immunol. 13, 417–435 (1995).

    Article  CAS  Google Scholar 

  11. MacLennan, I. C. M. Germinal centers. Annu. Rev. Immunol. 12, 117–139 (1994).

    Article  CAS  Google Scholar 

  12. Nishina, H. et al. Impaired CD28-mediated interleukin 2 production and proliferation in stress kinase SAPK/ERK1 kinase (SEK1)/mitogen-activated protein kinase kinase 4 (MKK4)-deficient T lymphocytes. J. Exp. Med. 186, 941–953 (1997).

    Article  CAS  Google Scholar 

  13. Mond, J. J., Lees, A. & Snapper, C. M. T cell-independent antigens type 2. Annu. Rev. Immunol. 13, 655–692 (1995).

    Article  CAS  Google Scholar 

  14. Snapper, C. M. & Paul, W. E. Interferon-γ and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science 236, 944–947 (1987).

    Article  ADS  CAS  Google Scholar 

  15. Finkelman, F. D. et al. Lymphokine control of in vivo immunoglobulin isotype selection. Annu. Rev. Immunol. 8, 303– 333 (1990).

    Article  CAS  Google Scholar 

  16. Snapper, C. M., Finkelman, F. D. & Paul, W. E. Regulation of IgG1 and IgE production by interleukin 4. Immunol. Rev. 102, 51– 75 (1988).

    Article  CAS  Google Scholar 

  17. Mosmann, T. R. & Coffman, R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145– 173 (1989).

    Article  CAS  Google Scholar 

  18. O'Garra, A. Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8, 275– 283 (1998).

    Article  CAS  Google Scholar 

  19. Kopf, M. et al. Inducible costimulator protein (ICOS) controls T helper cell subset polarization after virus and parasite infection. J. Exp. Med. 192, 53–61 ( 2000).

    Article  CAS  Google Scholar 

  20. Ferguson, S. E., Han, S., Kelsoe, G. & Thompson, C. B. CD28 is required for germinal center formation. J. Immunol. 156, 4576–4581 (1996).

    CAS  PubMed  Google Scholar 

  21. Xu, J. et al. Mice deficient for the CD40 ligand. Immunity 1, 423–431 (1994).

    Article  CAS  Google Scholar 

  22. Renshaw, B. R. et al. Humoral immune responses in CD40 ligand-deficient mice. J. Exp. Med. 180, 1889–1900 (1994).

    Article  CAS  Google Scholar 

  23. Shahinian, A. et al. Differential T cell costimulatory requirements in CD28-deficient mice . Science. 261, 609– 612 (1993).

    Article  ADS  CAS  Google Scholar 

  24. Grewal, I. S. & Flavell, R. A. The CD40 ligand: at the center of the immune universe? Immunol. Res. 16, 59–70 (1997).

    Article  CAS  Google Scholar 

  25. Metzler, W. J. et al. Solution structure of human CTLA-4 and delineation of a CD80/CD86 binding site conserved in CD28. Nature Struct. Biol. 4, 527–531.

    Article  CAS  Google Scholar 

  26. Prasad, K. V. et al. T-cell antigen CD28 interacts with the lipid kinase phosphatidylinositol 3-kinase by a cytoplasmic Tyr(P)-Met-Xaa-Met motif. Proc. Natl Acad. Sci. USA 91, 2834–2838 (1994).

    Article  ADS  CAS  Google Scholar 

  27. Stampfli, M. R. et al. Regulation of allergic mucosal sensitization by interleukin-12 gene transfer to the airway. Am. J. Respir. Cell. Mol. Biol. 21, 317–326 (1999).

    Article  CAS  Google Scholar 

  28. Ohkawara, Y. et al. Cytokine and eosinophil responses in the lung, peripheral blood, and bone marrow compartments in a murine model of allergen-induced airways inflammation. Am. J. Respir. Cell. Mol. Biol. 16, 510–520 (1997).

    Article  CAS  Google Scholar 

  29. Kuhn, R., Rajewsky, K. & Muller, W. Generation and analysis of interleukin-4 deficient mice. Science 254, 707–710 (1991).

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Goncharova, J. Haight and C. Smith for technical assistance; M. Pintilie and T. Panzarella for statistical analysis of the data; M. Saunders for scientific editing; K. Bachmaier for critical reading of the manuscript; V. Stambolic and L. Nguyen for comments and advice; and I. Ng for administrative assistance. This work was supported by the Canadian Institutes of Health Research, Amgen Inc., and Canadian Network for Vaccines and Immunotherapeutics of Cancer and Chronic Viral Diseases.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tak W. Mak.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tafuri, A., Shahinian, A., Bladt, F. et al. ICOS is essential for effective T-helper-cell responses. Nature 409, 105–109 (2001). https://doi.org/10.1038/35051113

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35051113

This article is cited by

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

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