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

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

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76 Citations (Scopus)


CTLA-4 is a crucial immune regulator that mediates both negative co-stimulation signals to T cells, and regulatory T (Tr) cell extrinsic control of effector responses. 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. Tr 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
Number of pages12
JournalEuropean Journal of Immunology
Issue number5
Early online date6 Mar 2013
Publication statusPublished - May 2013


  • costimulation
  • regulatory cells
  • CTLA-4 polymorphisms
  • CD4+ T cells
  • costimulatory molecules
  • immune regulation
  • Treg cells


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