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.
- MeSH
- Citrobacter rodentium imunologie MeSH
- enterobakteriální infekce genetika imunologie MeSH
- homeostáza účinky léků genetika imunologie MeSH
- lymfocyty účinky léků imunologie MeSH
- myši inbrední C57BL MeSH
- myši transgenní MeSH
- myši MeSH
- přirozená imunita * účinky léků genetika MeSH
- regulace genové exprese účinky léků MeSH
- signální transdukce účinky léků genetika MeSH
- střeva účinky léků imunologie mikrobiologie MeSH
- transkripční faktory Krüppel-like genetika fyziologie MeSH
- tretinoin metabolismus farmakologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The intestine is a unique immune environment that must respond to infectious organisms but remain tolerant to commensal microbes and food antigens. However, the molecular mechanisms that regulate immune cell function in the intestine remain unclear. Here we identify the POK/ZBTB family transcription factor hypermethylated in cancer 1 (HIC1, ZBTB29) as a central component of immunity and inflammation in the intestine. HIC1 is specifically expressed in immune cells in the intestinal lamina propria (LP) in the steady state and mice with a T-cell-specific deletion of HIC1 have reduced numbers of T cells in the LP. HIC1 expression is regulated by the Vitamin A metabolite retinoic acid, as mice raised on a Vitamin A-deficient diet lack HIC1-positive cells in the intestine. HIC1-deficient T cells overproduce IL-17A in vitro and in vivo, and fail to induce intestinal inflammation, identifying a critical role for HIC1 in the regulation of T-cell function in the intestinal microenvironment under both homeostatic and inflammatory conditions.
- MeSH
- homeostáza MeSH
- imunita MeSH
- interleukin-17 metabolismus MeSH
- kultivované buňky MeSH
- myši transgenní MeSH
- myši MeSH
- regulace genové exprese MeSH
- represorové proteiny metabolismus MeSH
- sliznice fyziologie MeSH
- střeva fyziologie MeSH
- T-lymfocyty fyziologie MeSH
- transkripční faktory Krüppel-like genetika metabolismus MeSH
- tretinoin metabolismus MeSH
- zánět imunologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH