Nuclear factor of activated T cells and AP-1 are insufficient for IL-2 promoter activation: requirement for CD28 up-regulation of RE/AP.
IL-2 gene transcription in T cells requires both TCR and costimulatory signals. IL-2 promoter activation in Jurkat T cells stimulated with superantigen presented by Raji B cells requires CD28 activation. The addition of rCTLA4Ig, which blocks CD28 binding to its ligand, to the cultures decreased IL-2 promoter activation by >80%. Interestingly, CTLA4Ig did not significantly inhibit the activation of either NF of activated T cells (NFAT) or AP-1 reporters. Therefore, activation of NFAT and AP-1 is insufficient for IL-2 promoter activation. In contrast, an RE/AP reporter was blocked by CTLA4Ig by >90%. Thus, the requirement for CD28 in IL-2 promoter activation appears to be due to RE/AP and not the NFAT or AP-1 sites. In addition, these data suggest that transcriptional activation of RE/AP is not mediated by NFAT, because activation of a NFAT reporter is not affected by the addition of CTLA4Ig.
Shapiro
V S
VS
Department of Medicine, University of California, San Francisco 94143, USA.
Mollenauer
M N
MN
Weiss
A
A
D000069594:Abatacept; D000942:Antigens, Bacterial / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000473:pathology; D018106:CD28 Antigens / Q000502:physiology*; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D004768:Enterotoxins / Q000276:immunology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D018796:Immunoconjugates; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D019169:Jurkat Cells; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation; D008214:Lymphocytes; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D018089:Superantigens / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000942:Antigens, Bacterial; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D004268:DNA-Binding Proteins; D004768:Enterotoxins; D018796:Immunoconjugates; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D018089:Superantigens; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C049463:enterotoxin E, Staphylococcal; D000069594:Abatacept; D008156:Luciferases; D016559:Tacrolimus