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J Immunol. 2014 Jul 15;193(2):889-900. doi: 10.4049/jimmunol.1303389. Epub 2014 Jun 13.

Investigation of soluble and transmembrane CTLA-4 isoforms in serum and microvesicles.

Author information

1
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom; National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and.
2
National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom.
3
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom; National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and linda.wicker@cimr.cam.ac.uk.

Abstract

Expression of the CTLA-4 gene is absolutely required for immune homeostasis, but aspects of its molecular nature remain undefined. In particular, the characterization of the soluble CTLA-4 (sCTLA-4) protein isoform generated by an alternatively spliced mRNA of CTLA4 lacking transmembrane-encoding exon 3 has been hindered by the difficulty in distinguishing it from the transmembrane isoform of CTLA-4, Tm-CTLA-4. In the current study, sCTLA-4 has been analyzed using novel mAbs and polyclonal Abs specific for its unique C-terminal amino acid sequence. We demonstrate that the sCTLA-4 protein is secreted at low levels following the activation of primary human CD4(+) T cells and is increased only rarely in the serum of autoimmune patients. Unexpectedly, during our studies aimed to define the kinetics of sCTLA-4 produced by activated human CD4(+) T cells, we discovered that Tm-CTLA-4 is associated with microvesicles produced by the activated cells. The functional roles of sCTLA-4 and microvesicle-associated Tm-CTLA-4 warrant further investigation, especially as they relate to the multiple mechanisms of action described for the more commonly studied cell-associated Tm-CTLA-4.

PMID:
24928993
PMCID:
PMC4082723
DOI:
10.4049/jimmunol.1303389
[Indexed for MEDLINE]
Free PMC Article

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