CD4 T cell lineage choice epitomises the ability of the immune system to become tailored to a specific threat and provides a framework for understanding the mechanisms behind cell specification. The differentiation of T effectors from naïve cells gives rise to pro-inflammatory lineages including T helper 1 (Th1) and Th2 and anti-inflammatory regulatory T cells (Treg). An additional lineage of Treg also exits the thymus in parallel to naïve T cells and together these Treg are required for prevention of autoimmunity. These T cell lineages are distinct in terms of their cytokine production and functional effects but also through their differences in gene expression and its regulation, which are orchestrated by the presence of lineage-specifying transcription factors specific for each lineage. In addition, post-translational modification of histones also provide insights into this transcriptional regulation and more recently the pervasive and tissue-specific transcription of multiple classes of RNA species without protein coding capacity, non-coding RNA (ncRNA), has been found to play a role in cell differentiation and function. In this thesis I identify several ncRNAs with differential expression different T cell lineages. This includes ncRNAs upregulated Treg compared to T responders. The characterisation of these, including their expression in the autoimmune context of systemic lupus erythematosus (SLE), is presented and their possible biological functions are examined. The relevance of histone modifications for influencing Treg identity in SLE is also investigated. An additional class of ncRNAs that originate from gene enhancer regions, eRNA, is also investigated in the context of Th1 versus Th2 lineage choice. This enhancer transcription is increased genome-wide in Th1 cells at enhancers with high density T-bet binding in, termed ‘super-enhancers’. The functional relevance of these eRNAs, including at the super-enhancer upstream of the Th1 signature cytokine gene, IFNG, is also investigated in knockdown experiments.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:654669 |
| Date | January 2015 |
| Creators | Evans, C. M. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1466165/ |
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