title: Transcriptional control of rapid recall by memory CD4 T cells.
abstract: Memory T cells are distinguished from naive T cells by their rapid production of effector cytokines, although mechanisms for this recall response remain undefined. In this study, we investigated transcriptional mechanisms for rapid IFN-γ production by Ag-specific memory CD4 T cells. In naive CD4 T cells, IFN-γ production only occurred after sustained Ag activation and was associated with high expression of the T-bet transcription factor required for Th1 differentiation and with T-bet binding to the IFN-γ promoter as assessed by chromatin immunoprecipitation analysis. By contrast, immediate IFN-γ production by Ag-stimulated memory CD4 T cells occurred in the absence of significant nuclear T-bet expression or T-bet engagement on the IFN-γ promoter. We identified rapid induction of NF-κB transcriptional activity and increased engagement of NF-κB on the IFN-γ promoter at rapid times after TCR stimulation of memory compared with naive CD4 T cells. Moreover, pharmacologic inhibition of NF-κB activity or peptide-mediated inhibition of NF-κB p50 translocation abrogated early memory T cell signaling and TCR-mediated effector function. Our results reveal a molecular mechanism for memory T cell recall through enhanced NF-κB p50 activation and promoter engagement, with important implications for memory T cell modulation in vaccines, autoimmunity, and transplantation.
authors.affiliation: Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Lai
authors.forename: Minjun
authors.initials: M
authors.lastname: Yu
authors.forename: Min-Nung
authors.initials: MN
authors.lastname: Huang
authors.forename: Francesca
authors.initials: F
authors.lastname: Okoye
authors.forename: Achsah D
authors.initials: AD
authors.lastname: Keegan
authors.forename: Donna L
authors.initials: DL
authors.lastname: Farber
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D003720:Densitometry; D007156:Immunologic Memory / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D052002:NF-kappa B p50 Subunit / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D010047:Ovalbumin / Q000276:immunology / Q000493:pharmacokinetics / Q000502:physiology; D010446:Peptide Fragments / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000276:immunology; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000276:immunology; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D000098815:T-bet Transcription Factor
chemical_list: D052002:NF-kappa B p50 Subunit; C111390:OVA 323-339; D010446:Peptide Fragments; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma; D010047:Ovalbumin