title: CTLA-4 up-regulation of lymphocyte function-associated antigen 1 adhesion and clustering as an alternate basis for coreceptor function.
abstract: Although cytotoxic T lymphocyte antigen-4 (CTLA-4) negatively regulates T cell activation, the full range of functions mediated by this coreceptor has yet to be established. In this study, we report the surprising finding that CTLA-4 engagement by soluble antibody or CD80 potently up-regulates lymphocyte function-associated antigen 1 (LFA-1) adhesion to intercellular adhesion molecule-1 (ICAM-1) and receptor clustering concurrent with IL-2 inhibition. This effect was also observed with CTLA-4 ligation and not with other coreceptors. T cell antigen receptor (TcR)-induced lymphocyte function-associated antigen 1 function was also dependent on CTLA-4 expression as observed with reduced adhesion/clustering on CTLA-4(-/-) primary T cells. CTLA-4 up-regulated adhesion was mediated by regulator for cell adhesion and polarization type 1 (Rap-1) as shown by anti-CTLA-4-induced Rap-1 activation as well as Rap-1-N17 blockade and Rap-1-V12 mimicry of adhesion/clustering. Our findings identify a potent role for CTLA-4 in directing integrin adhesion and provide an alternate mechanism to account for aspects of CTLA-4 function in T cell immunity.
authors.affiliation: Molecular Immunology Section, Department of Immunology, Division of Investigative Sciences, Faculty of Medicine, Imperial College London, Hammersmith Campus, London W12 ONN, United Kingdom.
authors.forename: Helga
authors.initials: H
authors.lastname: Schneider
authors.forename: Elke
authors.initials: E
authors.lastname: Valk
authors.forename: Silvy
authors.initials: S
authors.lastname: da Rocha Dias
authors.forename: Bin
authors.initials: B
authors.lastname: Wei
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Rudd
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen; D002448:Cell Adhesion; D002460:Cell Line; D016023:Integrins / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D012995:Solubility; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D000267:Tissue Adhesions; D015854:Up-Regulation; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D011948:Receptors, Antigen, T-Cell; D020827:rap1 GTP-Binding Proteins