title: In vivo anergized CD4+ T cells express perturbed AP-1 and NF-kappa B transcription factors.
abstract: Anergy is a major mechanism to ensure antigen-specific tolerance in T lymphocytes in the adult. In vivo, anergy has mainly been studied at the cellular level. In this study, we used the T-cell-activating superantigen staphylococcal enterotoxin A (SEA) to investigate molecular mechanisms of T-lymphocyte anergy in vivo. Injection of SEA to adult mice activates CD4+ T cells expressing certain T-cell receptor (TCR) variable region beta-chain families and induces strong and rapid production of interleukin 2 (IL-2). In contrast, repeated injections of SEA cause CD4+ T-cell deletion and anergy in the remaining CD4+ T cells, characterized by reduced expression of IL-2 at mRNA and protein levels. We analyzed expression of AP-1, NF-kappa B, NF-AT, and octamer binding transcription factors, which are known to be involved in the regulation of IL-2 gene promoter activity. Large amounts of AP-1 and NF-kappa B and significant quantities of NF-AT were induced in SEA-activated CD4+ spleen T cells, whereas Oct-1 and Oct-2 DNA binding activity was similar in both resting and activated T cells. In contrast, anergic CD4+ T cells contained severely reduced levels of AP-1 and Fos/Jun-containing NF-AT complexes but expressed significant amounts of NF-kappa B and Oct binding proteins after SEA stimulation. Resolution of the NF-kappa B complex demonstrated predominant expression of p50-p65 heterodimers in activated CD4+ T cells, while anergic cells mainly expressed the transcriptionally inactive p50 homodimer. These alterations of transcription factors are likely to be responsible for repression of IL-2 in anergic T cells.
authors.affiliation: Pharmacia Oncology Immunology, Lund, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Sundstedt
authors.forename: M
authors.initials: M
authors.lastname: Sigvardsson
authors.forename: T
authors.initials: T
authors.lastname: Leanderson
authors.forename: G
authors.initials: G
authors.lastname: Hedlund
authors.forename: T
authors.initials: T
authors.lastname: Kalland
authors.forename: M
authors.initials: M
authors.lastname: Dohlsten
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D017635:Clonal Anergy; D004768:Enterotoxins / Q000494:pharmacology; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000096:biosynthesis*; D009838:Oligodeoxyribonucleotides; D011401:Promoter Regions, Genetic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D018089:Superantigens / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000096:biosynthesis*; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D004768:Enterotoxins; D007369:Interferon Inducers; D007376:Interleukin-2; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C026066:enterotoxin A, Staphylococcal