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

Frank J Ward, Lekh N Dahal, Subadra K Wijesekera, Sultan K Abdul-Jawad, Taniya Kaewarpai, Heping Xu, Mark A Vickers, Robert N Barker

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50 Citations (Scopus)


CTLA-4 is a crucial immune regulator that mediates both negative co-stimulation 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 antigen-driven proliferation and cytokine (interferon-?, 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 antigen 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.
Original languageEnglish
Pages (from-to)1274-1285
JournalEuropean Journal of Immunology
Issue number5
Early online date06 Mar 2013
Publication statusPublished - 06 Mar 2013

Bibliographical note

© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


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