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
• Názvy látek
• Hic1 protein, mouse MeSH Prohlížeč
• transkripční faktory Krüppel-like MeSH
• tretinoin 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
• práce podpořená grantem MeSH
• Názvy látek
• Hic1 protein, mouse MeSH Prohlížeč
• interleukin-17 MeSH
• represorové proteiny MeSH
• transkripční faktory Krüppel-like MeSH
• tretinoin MeSH

Clinical response to methotrexate (MTX) treatment for children with juvenile idiopathic arthritis (JIA) displays considerable heterogeneity. Currently, there are no reliable predictors to identify non-responders: earlier identification could lead to a targeted treatment. We genotyped 759 JIA cases from the UK, the Netherlands and Czech Republic. Clinical variables were measured at baseline and 6 months after start of the treatment. In Phase I analysis, samples were analysed for the association with MTX response using ordinal regression of ACR-pedi categories and linear regression of change in clinical variables, and identified 31 genetic regions (P<0.001). Phase II analysis increased SNP density in the most strongly associated regions, identifying 14 regions (P<1 × 10(-5)): three contain genes of particular biological interest (ZMIZ1, TGIF1 and CFTR). These data suggest a role for novel pathways in MTX response and further investigations within associated regions will help to reach our goal of predicting response to MTX in JIA.

• MeSH
• dítě MeSH
• jednonukleotidový polymorfismus MeSH
• juvenilní artritida farmakoterapie   genetika   MeSH
• kohortové studie MeSH
• lidé MeSH
• methotrexát terapeutické užití   MeSH
• předškolní dítě MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• methotrexát MeSH