Development, regulation and function of human T helper 17 cells

• Main Author: Crome, Sarah Anne
• Language: English
• Published: University of British Columbia 2011
• Online Access: http://hdl.handle.net/2429/33078

Adaptive immunity is controlled by CD4+ T cells that develop into functionally distinct T helper (Th) cell subsets. The paradigm that cellular immunity is mediated by Th1 cells and humoral immunity by Th2 cells has been revised upon the discovery of a third Th lineage which produces Interleukin (IL)-17 (Th17 cells). Th17 cells exhibit a unique cytokine profile compared to other Th subsets and are important for host defense against extracellular pathogens. However, aberrant expansion of Th17 cells is linked to several autoimmune diseases including rheumatoid arthritis, psoriasis, inflammatory bowel disease and multiple sclerosis. Due to their association with dysregulated immune responses, there has been intense interest in understanding factors regulating Th17 cell development, phenotype and function. The findings herein identify several mechanisms which regulate this lineage. First, I identified a central role for a transcription factor known as retinoic acid-related orphan receptor C isoform 2 (RORC2) in the development of human Th17 cells. In order to study in vivo derived Th17 cells, a flow cytometry-based sorting method was established to isolate Th17 cells directly from peripheral blood. After defining the phenotype of these bona fide Th17 cells, I investigated their interactions with T regulatory (Treg) cells. Contrary to prior findings and RORC2 overexpression studies, Treg cells were potent inhibitors of in vivo-derived Th17 cell proliferation and suppressed their inflammatory mediators. To examine the stability of this lineage, a comprehensive study of the epigenetic phenotype of Th17 cells was performed. Further to defining Th17 cell’s epigenetic profile, examination of epigenetic marks following exposure to potent polarization conditions suggests Th17 cells are resistant to lineage conversion. Taken together, these findings provide an in-depth examination of this inflammatory T cell subset, provide new tools to study Th17 cells and elucidate mechanisms that regulate Th17 cells, thereby providing insights to aid development of therapeutic strategies for Th17-associated disorders.