title: Investigation of soluble and transmembrane CTLA-4 isoforms in serum and microvesicles.
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.
authors.affiliation: 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.
authors.forename: Laura
authors.initials: L
authors.lastname: Esposito
authors.affiliation: 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.
authors.forename: Kara M D
authors.initials: KM
authors.lastname: Hunter
authors.affiliation: 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.
authors.forename: Jan
authors.initials: J
authors.lastname: Clark
authors.affiliation: 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.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Rainbow
authors.affiliation: 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.
authors.forename: Helen
authors.initials: H
authors.lastname: Stevens
authors.affiliation: 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.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Denesha
authors.affiliation: 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.
authors.forename: Simon
authors.initials: S
authors.lastname: Duley
authors.affiliation: 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.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dawson
authors.affiliation: 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.
authors.forename: Gillian
authors.initials: G
authors.lastname: Coleman
authors.affiliation: 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.
authors.forename: Sarah
authors.initials: S
authors.lastname: Nutland
authors.affiliation: 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.
authors.forename: Gwynneth L
authors.initials: GL
authors.lastname: Bell
authors.affiliation: 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.
authors.forename: Carla
authors.initials: C
authors.lastname: Moran
authors.affiliation: 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.
authors.forename: Marcin
authors.initials: M
authors.lastname: Pekalski
authors.affiliation: 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.
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.affiliation: 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.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wicker
mesh_terms: D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D060908:CTLA-4 Antigen / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D022162:Cytoplasmic Vesicles / Q000378:metabolism* / Q000648:ultrastructure; D003922:Diabetes Mellitus, Type 1 / Q000097:blood; D005260:Female; D006111:Graves Disease / Q000097:blood; D006367:HeLa Cells; D006801:Humans; D007118:Immunoassay; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012995:Solubility; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D008562:Membrane Glycoproteins; D020033:Protein Isoforms