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ICOS is critical for CD40-mediated antibody class switching

Nature volume 409, pages 102–105 (2001)Cite this article

Abstract

The inducible co-stimulatory molecule (ICOS) is a CD28 homologue implicated in regulating T-cell differentiation1,2,3,4,5. Because co-stimulatory signals are critical for regulating T-cell activation, an understanding of co-stimulatory signals may enable the design of rational therapies for immune-mediated diseases6. According to the two-signal model for T-cell activation, T cells require an antigen-specific signal and a second, co-stimulatory, signal for optimal T-cell activation6. The co-stimulatory signal promotes T-cell proliferation, lymphokine secretion and effector function. The B7–CD28 pathway provides essential signals for T-cell activation, but does not account for all co-stimulation. We have generated mice lacking ICOS (ICOS-/-) to determine the essential functions of ICOS. Here we report that ICOS-/- mice exhibit profound deficits in immunoglobulin isotype class switching, accompanied by impaired germinal centre formation. Class switching was restored in ICOS-/- mice by CD40 stimulation, showing that ICOS promotes T-cell/B-cell collaboration through the CD40/CD40L pathway.

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Figure 1: Generation of ICOS-/- mice.
Figure 2: Antibody responses and GCs in ICOS-/- mice.
Figure 3: The role of CD40 in ICOS mediated antibody class switching.
Figure 4: T-cell responses in ICOS-/- mice a, CD4+ cells from ICOS+/+ (filled squares) or ICOS-/- (open squares) mice were stimulated with APCs from wild-type or B7-1/2-/- APC and anti-CD3 for 2 d.

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Acknowledgements

This work was supported by grants from Genetics Institute (to A.H.S.) and the NIH (to A.J.M., R.J.G., G.J.F. and A.H.S.). We thank M. Collins for thoughtful discussions, and L. Du, J. Burgess and B. Chang for technical support.

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Author notes

  1. Gordon J. Freeman and Arlene H. Sharpe: These authors contributed equally to this work

Authors and Affiliations

  1. Departments of Pathology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Alexander J. McAdam, Rebecca J. Greenwald, Michele A. Levin & Arlene H. Sharpe

  2. Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, 02115, Massachusetts, USA

    Tatyana Chernova, Nelly Malenkovich & Gordon J. Freeman

  3. Department of Immunology, Genetics Institute, 87 CambridgePark Drive, Cambridge, 02081, Massachusetts, USA

    Vincent Ling

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  1. Alexander J. McAdam
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Correspondence to Arlene H. Sharpe.

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McAdam, A., Greenwald, R., Levin, M. et al. ICOS is critical for CD40-mediated antibody class switching. Nature 409, 102–105 (2001). https://doi.org/10.1038/35051107

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