T-cells coordinate the immune response. Appropriate immunity is essential for effective host responses to respiratory pathogens such as influenza virus and Mycobacterium tuberculosis. T-cell immunodeficiency in advanced HIV disease confers susceptibility to opportunistic infections such as pneumocystiis carinii and Mycobacterium avium. Excessive lung inflammation in response to influenza virus can produce adult respiratory distress syndrome and respiratory failure. Activation of T-cells induces the production of T-cell growth and survival factor, IL-2. Regulatory T-cells intrinsically fail to induce IL-2 expression upon activation and can suppress IL-2 production in conventional T-cells. Thus, the control of IL-2 expression is critically important to T-cell immune responses, yet the mechanisms remain incompletely understood. T-cell activation triggered through antigen and CD28 receptors induces epigenetic modifications of histones including acetylation and methylation, DMA demethylation, nucleosome disruption, concerted binding of transcription factors to the IL-2 proximal promoter and IL-2 transcription. NF90 is a zinc finger DNA- and double-stranded RNA binding protein subunit that binds specifically and inducibly to the antigen receptor response element/NF-AT target sequence in the IL-2 proximal promoter, as shown by chromatin immunoprecipitation. NF90 possesses intrinsic histone acetyltransferase (HAT) activity. The hypothesis to be tested is that epigenetic modifications of histones at the IL-2 promoter that regulate chromatin remodeling and transcriptional activation involve the HAT activity of NF90. The hypothesis will be tested that FoxP3 expression in regulatory T-cells interferes with epigenetic modifications that regulate IL-2 chromatin remodeling and transcriptional activation.
The aims are to: 1) Characterize epigenetic modifications of histones, DNA and transcription factors associated with IL-2 chromatin remodeling during T-cell activation, 2) Characterize the role of NF90 HAT activity in IL-2 activation, 3) Characterize how FoxP3 regulates epigenetic modifications and chromatin remodeling at the IL-2 proximal promoter and other promoters. Further molecular insights into the regulation of IL-2 gene expression in activated T-cells will identify novel targets and strategies for therapeutic manipulation of T-cell immune responses in disease.
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