Transcriptional regulation of human T cell differentiation. (360G-Wellcome-091009_B_09_Z)

CD4+ T cells differentiate into a number of effector types that define the immune response to different pathogens. Differentiation into specialized effectors is linked to changes in chromatin structure at key genes and transcription factors have been identified that are critical for this process. These epigenetic modifications provide a memory of cellular state passed onto cellular descendents. T cell effector types are also remarkably plastic and this combination of specificity and plasticity i s likely to be critical for the normal regulation of T cell effector function. We will identify the changes in histone methylation that occur across the genome during differentiation of primary human CD4+ T cells. We will test the hypothesis that lineage-specific gene expression is regulated primarily at the level of transcriptional elongation and determine the role of master regulator transcription factors. From these data, we will develop a conceptual framework that explains the specificity an d plasticity of the helper T cell response. All aspects of this proposal are underpinned by significant amounts of preliminary data. We will define these mechanisms with a combination of established in vitro and in vivo genomic, genetic and biochemical methods and this work will significantly enhance our understanding of human disease processes.