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CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator

A Corrigendum to this article was published on 01 May 2008

This article has been updated

Abstract

CD160, a glycosylphosphatidylinositol-anchored member of the immunoglobulin superfamily, is expressed on both cytolytic lymphocytes and some unstimulated CD4+ T cells. Here we show that CD160 expression was increased after activation of human CD4+ T cells and that crosslinking CD160 with monoclonal antibody strongly inhibited CD3- and CD28-mediated activation. We found that herpesvirus entry mediator (HVEM) was a ligand of CD160 that acted as a 'bidirectional switch' for T cell activation, producing a positive or negative outcome depending on the engagement of HVEM by CD160 and known HVEM ligands such as B and T lymphocyte attenuator (BTLA) and the T lymphocyte receptor LIGHT. Inhibition of CD4+ T cell activation by HVEM-transfected cells was dependent on CD160 and BTLA; when the cysteine-rich domain 1 of HVEM was deleted, this inhibition was lost, resulting in strong T cell activation. CD160 thus serves as a negative regulator of CD4+ T cell activation through its interaction with HVEM.

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Figure 1: Expression of CD160 on transfectants and CD4+ and CD8+ T cell populations.
Figure 2: Crosslinking of CD160 inhibits CD4+ T cell activation.
Figure 3: Engagement of CD160 inhibits the tyrosine phosphorylation of several proteins induced by anti-CD3 and anti-CD28.
Figure 4: Cloning of HVEM as a CD160 ligand.
Figure 5: Interaction of HVEM with CD160, BTLA and LIGHT.
Figure 6: Both CD160 and BTLA inhibit CD4+ T cell activation.
Figure 7: HVEM-transfected NIH-3T3 cells inhibit CD4+ T cell activation and inhibition can be reversed by anti–CD160 Fab or by deletion of CRD1 of HVEM.

Change history

  • 19 March 2008

    In the version of this article initially published, the citation for Supplementary Figure 2c on page 179 and the citation for Supplementary Figure 3a on page 180 are incorrect. These should be “Supplementary Fig. 2a–c” and “Supplementary Fig. 3,” respectively. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

Confocal images were obtained by T. Hickman (Brigham and Women's Confocal Core Facility). Supported by the National Institutes of Health (AI39671 and AI56299 to G.J.F.).

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Authors and Affiliations

Authors

Contributions

G.C. designed and did the experiments, analyzed the data and wrote the paper; A.A. prepared CD160-Ig and provided some of the initial ideas; J.A.B. prepared 2C1 T cells; E.A.G. generated mAbs to CD160; B.Z. prepared fusion protein and expression constructs; and G.J.F. planned and supervised the project, designed constructs and wrote the paper.

Note: Supplementary information is available on the Nature Immunology website.

Corresponding author

Correspondence to Gordon J Freeman.

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Competing interests

A.A. and G.J.F. have applied for a US patent concerning the CD160 genes and the uses thereof.

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Supplementary Figures 1–3, Supplementary Table 1 and Supplementary Methods (PDF 973 kb)

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Cai, G., Anumanthan, A., Brown, J. et al. CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator. Nat Immunol 9, 176–185 (2008). https://doi.org/10.1038/ni1554

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