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

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...

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Bibliographic Details
Published in:European journal of immunology 2013-05, Vol.43 (5), p.1274-1285
Main Authors: Ward, Frank J., Dahal, Lekh N., Wijesekera, Subadra K., Abdul‐Jawad, Sultan K., Kaewarpai, Taniya, Xu, Heping, Vickers, Mark A., Barker, Robert N.
Format: Article
Language:English
Subjects:
Animals
Antibodies, Neutralizing - pharmacology
CD4+ T cells
Cells, Cultured
Costimulatory molecules
CTLA-4 Antigen - antagonists & inhibitors
CTLA-4 Antigen - genetics
CTLA-4 Antigen - immunology
Female
Humans
Immune regulation
Interferon-gamma - biosynthesis
Interferon-gamma - immunology
Interleukin-17 - biosynthesis
Interleukin-17 - immunology
Lymphocytes
Medical research
Melanoma, Experimental - drug therapy
Melanoma, Experimental - genetics
Melanoma, Experimental - immunology
Melanoma, Experimental - pathology
Mice
Mice, Inbred BALB C
Neoplasm Metastasis - prevention & control
Protein Isoforms - antagonists & inhibitors
Protein Isoforms - genetics
Protein Isoforms - immunology
Signal Transduction - drug effects
Signal Transduction - immunology
Solubility
T-Lymphocytes, Cytotoxic - cytology
T-Lymphocytes, Cytotoxic - immunology
T-Lymphocytes, Cytotoxic - metabolism
T-Lymphocytes, Regulatory - cytology
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - metabolism
Treg cells
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Description
Summary: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.
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.201242529