Transcriptional control of rapid recall by memory CD4 T cells

• Published in: The Journal of immunology (1950) 2011-07, Vol.187 (1), p.133-140
• Main Authors: Lai, Wendy, Yu, Minjun, Huang, Min-Nung, Okoye, Francesca, Keegan, Achsah D, Farber, Donna L
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cells, Cultured; Densitometry; Immunologic Memory - genetics; Interferon-gamma - biosynthesis; Interferon-gamma - secretion; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Transgenic; Molecular Sequence Data; NF-kappa B p50 Subunit - biosynthesis; NF-kappa B p50 Subunit - genetics; NF-kappa B p50 Subunit - physiology; Ovalbumin - immunology; Ovalbumin - pharmacokinetics; Ovalbumin - physiology; Peptide Fragments - physiology; Promoter Regions, Genetic - immunology; Resting Phase, Cell Cycle - genetics; Resting Phase, Cell Cycle - immunology; T-Box Domain Proteins - biosynthesis; T-Box Domain Proteins - genetics; Transcription, Genetic - immunology; Up-Regulation - genetics; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1002742

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.