HIC1 links retinoic acid signalling to group 3 innate lymphoid cell-dependent regulation of intestinal immunity and homeostasis.

Kyle Burrows,Vladimir Korinek,Michael Bramhall,Alistair Chenery,Frann Antignano,T Michael Underhill,Colby Zaph,William C Gause

doi:10.1371/journal.ppat.1006869

Kyle Burrows, Vladimir Korinek + Show 6 more

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https://doi.org/10.1371/journal.ppat.1006869

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Abstract

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 innate lymphoid cell (ILC) responses in the intestine. However, the molecular mechanisms of atRA-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) that produce IL-22 are lost, resulting in increased susceptibility to infection with the bacterial pathogen Citrobacter rodentium. Thus, atRA-dependent expression of HIC1 in ILC3s regulates intestinal homeostasis and protective immunity.

Highlights

The intestinal immune system is held in a tightly regulated balance between immune activation in response to potential pathogens and the maintenance of tolerance to innocuous antigens, such as food and commensal flora
We show that the all-trans-retinoic acid (atRA)-dependent transcription factor Hypermethylated in cancer 1 (HIC1, ZBTB29) is required for innate lymphoid cell (ILC) homeostasis and function in the steady state as well as following infection with the bacterial pathogen Citrobacter rodentium
AtRA controls the development of ILC subsets in the intestine, as mice raised on a Vitamin A-deficient (VAD) diet display reduced numbers of ILC3s [10,11], with one study showing a concomitant increase in ILC2 numbers and enhanced type 2 immunity within the intestine [10]

Summary

Introduction

The intestinal immune system is held in a tightly regulated balance between immune activation in response to potential pathogens and the maintenance of tolerance to innocuous antigens, such as food and commensal flora. Disruption of this balance can lead to the development of serious inflammatory disorders, such as food allergy or inflammatory bowel disease (IBD). AtRA controls the development of ILC subsets in the intestine, as mice raised on a Vitamin A-deficient (VAD) diet display reduced numbers of ILC3s [10,11], with one study showing a concomitant increase in ILC2 numbers and enhanced type 2 immunity within the intestine [10]. The molecular mechanisms downstream of atRA signaling that control immune cell function and homeostasis remain unknown

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