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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.

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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

Author notes

    • Anna Tafuri
    • , Arda Shahinian
    •  & Friedhelm Bladt

    These authors contributed equally to this work

Affiliations

  1. †Amgen Institute, 620 University Avenue, Toronto, Ontario M5G 2C1, Canada

    • Anna Tafuri
    • , Arda Shahinian
    • , Andrew Wakeham
    • , Louis-Martin Boucher
    • , Denis Bouchard
    • , Gordon Duncan
    • , Alexandra Ho
    • , Annick Itie
    • , Josef M. Penninger
    •  & Tak W. Mak
  2. ‡Ontario Cancer Institute, and Departments of Medical Biophysics and Immunology, University of Toronto, Toronto , Ontario M5G 2C1, Canada

    • Anna Tafuri
    • , Arda Shahinian
    • , Andrew Wakeham
    • , Louis-Martin Boucher
    • , Denis Bouchard
    • , Vera S. F. Chan
    • , Gordon Duncan
    • , Alexandra Ho
    • , Annick Itie
    • , Josef M. Penninger
    • , Pamela S. Ohashi
    •  & Tak W. Mak
  3. §Mount Sinai Hospital, Samuel Lunenfeld Research Institute, 600 University Avenue, Toronto , Ontario M5G 1X5, Canada

    • Friedhelm Bladt
    •  & Tony Pawson
  4. Amgen, One Amgen Center Drive, Thousand Oaks, California 91320-1789 , USA

    • Steve K. Yoshinaga
    • , Tom Horan
    •  & John S. Whoriskey
  5. ¶Department of Pathology and Molecular Medicine, Faculty of Health Science, McMaster University, Hamilton , Ontario L8N 3Z5, Canada

    • Manel Jordana
  6. University Hospital Zurich, Department of Pathology, CH-8091 Zurich, Switzerland

    • Bernhard Odermatt

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Correspondence to Tak W. Mak.

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DOI

https://doi.org/10.1038/35051113

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