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

Kyle Burrows; Frann Antignano; Alistair Chenery; Michael Bramhall; Vladimir Korinek; T Michael Underhill; Colby Zaph

doi:10.1371/journal.ppat.1006869

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

PLoS Pathog. 2018 Feb 22;14(2):e1006869. doi: 10.1371/journal.ppat.1006869. eCollection 2018 Feb.

Authors

Kyle Burrows^{1

2}, Frann Antignano¹, Alistair Chenery^{1

2}, Michael Bramhall^{3

4}, Vladimir Korinek⁵, T Michael Underhill^{1

6}, Colby Zaph^{1

2

3

4}

Affiliations

¹ The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
² Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
³ Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
⁴ Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
⁵ Department of Cell and Developmental Biology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
⁶ The Department of Cellular & Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Citrobacter rodentium / immunology
Enterobacteriaceae Infections / genetics
Enterobacteriaceae Infections / immunology
Gene Expression Regulation / drug effects
Homeostasis / drug effects
Homeostasis / genetics
Homeostasis / immunology
Immunity, Innate* / drug effects
Immunity, Innate* / genetics
Intestines / drug effects*
Intestines / immunology*
Intestines / microbiology
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / physiology*
Lymphocytes / drug effects*
Lymphocytes / immunology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Signal Transduction / drug effects
Signal Transduction / genetics
Tretinoin / metabolism
Tretinoin / pharmacology*

Substances

Hic1 protein, mouse
Kruppel-Like Transcription Factors
Tretinoin

Grants and funding

Canadian Institutes of Health Research (www.cihr.ca), MSH-95368, MOP-89773, MOP-106623. National Health and Medical Research Council (www.nhmrc.org.au), APP1104433, APP1104466. veski (www.veski.org.au), VESKI-FA14. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.