PT  - JOURNAL ARTICLE
AU  - Kyle Burrows
AU  - Frann Antignano
AU  - Alistair Chenery
AU  - Vladimir Korinek
AU  - T. Michael Underhill
AU  - Colby Zaph
TI  - HIC1 links retinoic acid signalling to group 3 innate lymphoid cell-dependent regulation of intestinal immunity and homeostasis
AID  - 10.1101/108241
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 108241
4099  - http://biorxiv.org/content/early/2017/02/13/108241.short
4100  - http://biorxiv.org/content/early/2017/02/13/108241.full
AB  - 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 retinoic acid (RA) has been implicated in the regulation of this balance, partially by regulating innate lymphoid cell (ILC) responses in the intestine. However, the molecular mechanisms of RA-dependent intestinal immunity and homeostasis remain elusive. Here we define a role for the transcriptional repressor Hypermethylated in cancer 1 (HIC1, ZBTB29) in the regulation of ILC responses in the intestine. Intestinal ILCs express HIC1 in a vitamin A-dependent manner. In the absence of HIC1, group 3 ILCs (ILC3s) are lost, resulting in increased susceptibility to infection with the 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. Thus, RA-dependent expression of HIC1 in ILC3s regulates intestinal homeostasis and protective immunity.Author Summary Innate lymphoid cells (ILCs) are emerging as important regulators of immune responses at barrier sites such as the intestine. However, the molecular mechanisms that control this are not well described. In the intestine, the Vitamin A metabolite retinoic acid (RA) has been shown to be an important component of the homeostatic mechanisms. In this manuscript, we show that the RA-dependent transcription factor Hypermethylated in cancer 1 (HIC1, ZBTB29) is required for ILC homeostasis and function in the steady state as well as following infection with the bacterial pathogen Citrobacter rodentium or the helminth parasite Trichuris muris. Thus, HIC1 links RA signalling to intestinal immune responses. Further, our results identify HIC1 as a potential target to modulate ILC responses in vivo in health and disease.