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Title: The role of retinoic acid in the regulation of T helper welfare
Author: Brown, Chrysothemis Celia Margaret
ISNI:       0000 0004 7656 4590
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2018
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In response to antigenic stimulation and extrinsic cytokine signals CD4+ T cells differentiate into specialized effector T helper (Th) cell subsets. Regulation of plasticity between these CD4+ T-cell lineages is critical for immune homeostasis and prevention of autoimmune diseases. However, the factors that regulate lineage stability are largely unknown. In Chapter 2, retinoic acid (RA), the active metabolite of vitamin A, is shown to regulate the stability of T helper 1 (Th1) cells, traditionally considered the most phenotypically stable CD4+ T cell subset. Signaling through RA receptor α (RARα) sustains stable expression of Th1 lineage specifying genes, as well as repression of genes that instruct Th17 cell fate. RA signaling is shown to be critical for limiting Th1 cell conversion into Th17 effectors and for preventing pathogenic Th17 responses in vivo. These findings identify RA/RARα as a key component of the regulatory network governing maintenance and plasticity of Th1 cell fate and define a new pathway for the development of pathogenic Th17 cells. The molecular mechanisms underlying regulation of Th1 plasticity depend on the ability of RARα to recruit p300 to cis regulatory enhancers at key Th1 defining genes. Chapter 3 expands on these findings and examines a global role for RARα in the regulation of enhancers in both Th1 and Th17 cells. Strikingly, RARα is shown to be the dominant regulator of enhancer activation in Th1 cells. Comparison of RARα bound enhancers in T helper cell subsets reveal lineage specific RARα bound genes and provide a mechanistic basis for the cell context dependent effects of RA on T helper cell fate. Collectively, the data identify a fundamental role for RA synthesis and signaling in the epigenetic regulation of T helper cell fate and suggest a broader role for RARα in the regulation of enhancers outside of the immune system.
Supervisor: Lord, Graham Michael Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available