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
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
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
Similar content being viewed by others
References
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).
Lenschow, D. J., Walunas, T. L. & Bluestone, J. A. CD28/B7 system of T cell costimulation. Annu. Rev. Immunol. 14, 233–258 (1996).
Watts, T. H. & DeBenedette, M. A. T cell co-stimulatory molecules other than CD28. Cur. Opin. Immunol. 11, 286–293 (1999).
Hutloff, A. et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397, 263–266 (1999).
Yoshinaga, S. K. et al. T-cell co-stimulation through B7RP-1 and ICOS. Nature 402, 827–832 ( 1999).
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).
Aicher, A. et al. Characterization of human inducible costimulator ligand expression and function. J. Immunol. 164, 4689 –4696 (2000).
Coyle, A. J. et al. The CD28-related molecule ICOS is required for effective T cell-dependent immune responses. Immunity 13, 95–105 (2000).
Statistical Methods in the Pharmaceutical Industry 2nd edn (eds Buncher, C. R. & Tsay, J.-Y.) 517– 518 (Marcel Dekker, New York, 1994).
Grusby, M. J. & Glimcher, L. H. Immune responses in MHC class II-deficient mice. Annu. Rev. Immunol. 13, 417–435 (1995).
MacLennan, I. C. M. Germinal centers. Annu. Rev. Immunol. 12, 117–139 (1994).
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).
Mond, J. J., Lees, A. & Snapper, C. M. T cell-independent antigens type 2. Annu. Rev. Immunol. 13, 655–692 (1995).
Snapper, C. M. & Paul, W. E. Interferon-γ and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science 236, 944–947 (1987).
Finkelman, F. D. et al. Lymphokine control of in vivo immunoglobulin isotype selection. Annu. Rev. Immunol. 8, 303– 333 (1990).
Snapper, C. M., Finkelman, F. D. & Paul, W. E. Regulation of IgG1 and IgE production by interleukin 4. Immunol. Rev. 102, 51– 75 (1988).
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).
O'Garra, A. Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8, 275– 283 (1998).
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).
Ferguson, S. E., Han, S., Kelsoe, G. & Thompson, C. B. CD28 is required for germinal center formation. J. Immunol. 156, 4576–4581 (1996).
Xu, J. et al. Mice deficient for the CD40 ligand. Immunity 1, 423–431 (1994).
Renshaw, B. R. et al. Humoral immune responses in CD40 ligand-deficient mice. J. Exp. Med. 180, 1889–1900 (1994).
Shahinian, A. et al. Differential T cell costimulatory requirements in CD28-deficient mice . Science. 261, 609– 612 (1993).
Grewal, I. S. & Flavell, R. A. The CD40 ligand: at the center of the immune universe? Immunol. Res. 16, 59–70 (1997).
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.
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).
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).
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).
Kuhn, R., Rajewsky, K. & Muller, W. Generation and analysis of interleukin-4 deficient mice. Science 254, 707–710 (1991).
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
Corresponding author
Rights 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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/35051113
This article is cited by
-
The relationship between peripheral T follicular helper cells and disease severity in systemic sclerosis
Clinical and Experimental Medicine (2024)
-
The ubiquitin ligase Peli1 inhibits ICOS and thereby Tfh-mediated immunity
Cellular & Molecular Immunology (2021)
-
Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies
Nature Communications (2020)
-
Transmembrane domain-mediated Lck association underlies bystander and costimulatory ICOS signaling
Cellular & Molecular Immunology (2020)
-
The promise and challenges of immune agonist antibody development in cancer
Nature Reviews Drug Discovery (2018)
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.