The soluble isoform of CTLA-4 as a regulator of T-cell responses

Authors

  • Frank J. Ward,

    Corresponding author
    • Section of Immunology and Infection, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
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    • These authors contributed equally to this work.

  • Lekh N. Dahal,

    1. Section of Immunology and Infection, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
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    • These authors contributed equally to this work.

  • Subadra K. Wijesekera,

    1. Section of Immunology and Infection, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
    Current affiliation:
    1. Open University of Sri Lanka, Kandy Regional Centre Polgolla, Sri Lanka
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  • Sultan K. Abdul-Jawad,

    1. Section of Immunology and Infection, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
    Current affiliation:
    1. The Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford, UK
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  • Taniya Kaewarpai,

    1. Section of Immunology and Infection, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
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  • Heping Xu,

    1. Section of Immunology and Infection, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
    Current affiliation:
    1. Centre for Vision and Vascular Science (CVVS), Institute of Clinical Science-A, Queen's University Belfast, Belfast, UK
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  • Mark A. Vickers,

    1. Section of Immunology and Infection, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
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  • Robert N. Barker

    1. Section of Immunology and Infection, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
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Full correspondence Dr. Frank J. Ward, Section of Immunology and Infection, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK

Fax: +44-1224 437348

e-mail: mmd475@abdn.ac.uk

Abstract

CTLA-4 is a crucial immune regulator that mediates both negative costimulation signals to T cells, and regulatory T (Treg)-cell extrinsic control of effector responses. Here we present evidence supporting a novel mechanism for this extrinsic suppression, executed by the alternatively spliced soluble CTLA-4 isoform (sCTLA-4). Analyses of human T cells in vitro show that sCTLA-4 secretion can be increased during responses, and has potent inhibitory properties, since isoform-specific blockade of its activity significantly increased Ag-driven proliferation and cytokine (IFN-γ, IL-17) secretion. Treg cells were demonstrated to be a prominent source of sCTLA-4, which contributed to suppression in vitro when their numbers were limiting. The soluble isoform was also produced by, and inhibited, murine T cells responding to Ag in vitro, and blockade of its activity in vivo protected against metastatic spread of melanoma in mice. We conclude that sCTLA-4 is an important immune regulator, responsible for at least some of the inhibitory effects previously ascribed to the membrane-bound isoform. These results suggest that the immune system exploits the different CTLA-4 isoforms for either intrinsic or extrinsic regulation of T-cell activity.

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