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.

Department of Biochemistry and Molecular Biology School of Biomedical Sciences Monash University Clayton Victoria Australia

Department of Cell and Developmental Biology Institute of Molecular Genetics Academy of Sciences of the Czech Republic Prague Czech Republic

Department of Pathology and Laboratory Medicine University of British Columbia Vancouver British Columbia Canada

Infection and Immunity Program Monash Biomedicine Discovery Institute Monash University Clayton Victoria Australia

The Biomedical Research Centre University of British Columbia Vancouver British Columbia Canada

The Department of Cellular and Physiological Sciences University of British Columbia Vancouver British Columbia Canada

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