Regulation of intestinal immune responses by the retinoic acid inducible transcription factor HIC1

• Main Author: Burrows, Kyle Aaron
• Language: English
• Published: University of British Columbia 2017
• Online Access: http://hdl.handle.net/2429/62108

The intestinal immune system must be able to respond to a wide variety of infectious organisms while maintaining tolerance to non-pathogenic microbes and food antigens. The Vitamin A metabolite all-trans-retinoic acid (atRA) has been implicated in the regulation of this balance, partially by regulating T cell and innate lymphoid cell (ILC) responses in the intestine. However, the molecular mechanisms of atRA-dependent intestinal immunity and homeostasis remain elusive. The work herein investigates the role for the POK/ZBTB family transcriptional repressor Hypermethylated in cancer 1 (HIC1, ZBTB29) in the regulation of immune cell responses in the intestine. Using genetically modified mice I demonstrate that Hic1 is specifically expressed in immune cells of the intestine at steady state in an atRA dependent manner. I further show that mice with a T cell-specific deletion of Hic1 have reduced numbers of T cells in the intestine. In addition, I demonstrate that HIC1-deficient T cells overproduce IL-17A in vitro and in vivo, and fail to induce intestinal inflammation in multiple murine models of inflammatory bowel disease, identifying a critical role for HIC1 in the regulation of T cell function in the intestinal microenvironment under both homeostatic and inflammatory conditions. In other studies, I investigated the cell-intrinsic role of HIC1 in intestinal ILC populations. I demonstrate that in the absence of HIC1, group 3 ILCs (ILC3s) are lost, resulting in increased susceptibility to infection with the murine bacterial pathogen Citrobacter rodentium. In addition, the loss of ILC3s leads to a local and systemic increase in IFN-γ-producing T cells that prevents the development of protective immunity against infection with the parasitic helminth Trichuris muris. Together the results presented here provide further insight into atRA mediated immune responses in the intestine as atRA-dependent expression of HIC1 in T cells and ILC3s regulate intestinal homeostasis, inflammation and protective immunity. === Medicine, Faculty of === Pathology and Laboratory Medicine, Department of === Graduate