title: IL-2-independent activation and proliferation in human T cells induced by CD28.
abstract: Although the role of CD28 in T cell costimulation is firmly established, the mechanisms by which it exerts its costimulatory actions are less clear. In many circumstances it is difficult to distinguish the effects of CD28 from subsequent actions of cytokines, such as IL-2, on T cell proliferation. Here, we report a model of CD28 costimulation using PMA plus the natural ligand CD80 that resulted in very limited stimulation of IL-2, as evidenced by both cytokine production and IL-2 promoter stimulation. Promoter assays revealed CD28-dependent effects on both NF-kappaB and AP-1, but not on NF-AT or the intact IL-2 promoter. In addition, T cell proliferation was completely resistant to the actions of the immunosuppressant cyclosporin A (CsA). Moreover T cell proliferation was unaffected by the addition of blocking Abs to both IL-2 and the IL-2 receptor, demonstrating that this form of costimulation by CD28 was independent of IL-2. We also investigated the effects of stimulating T cell blasts with CD80 alone and found that there was a limited requirement for IL-2 in this system. We conclude that CD28 costimulation can cause substantial T cell proliferation in the absence of IL-2, which is driven by a soluble factor independent of NF-AT transactivation.
authors.affiliation: Department of Pharmacology, University of Bath, United Kingdom.
authors.forename: G
authors.initials: G
authors.lastname: Boulougouris
authors.forename: J D
authors.initials: JD
authors.lastname: McLeod
authors.forename: Y I
authors.initials: YI
authors.lastname: Patel
authors.forename: C N
authors.initials: CN
authors.lastname: Ellwood
authors.forename: L S
authors.initials: LS
authors.lastname: Walker
authors.forename: D M
authors.initials: DM
authors.lastname: Sansom
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D018122:B7-1 Antigen / Q000494:pharmacology; D018106:CD28 Antigens / Q000502:physiology*; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D006224:Cricetinae; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics; D004351:Drug Resistance; D004357:Drug Synergism; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007399:Interphase / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D012995:Solubility; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D018122:B7-1 Antigen; D018106:CD28 Antigens; D016207:Cytokines; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D007376:Interleukin-2; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D015375:Receptors, Interleukin-2; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D016572:Cyclosporine; D013755:Tetradecanoylphorbol Acetate