In the past decade, single-cell transcriptomics has helped to uncover new cell types and states and led to the construction of a cellular compendium of health and disease. Despite this progress, some difficult-to-sequence cells remain absent from tissue atlases. Eosinophils-elusive granulocytes that are implicated in a plethora of human pathologies1-5-are among these uncharted cell types. The heterogeneity of eosinophils and the gene programs that underpin their pleiotropic functions remain poorly understood. Here we provide a comprehensive single-cell transcriptomic profiling of mouse eosinophils. We identify an active and a basal population of intestinal eosinophils, which differ in their transcriptome, surface proteome and spatial localization. By means of a genome-wide CRISPR inhibition screen and functional assays, we reveal a mechanism by which interleukin-33 (IL-33) and interferon-γ (IFNγ) induce the accumulation of active eosinophils in the inflamed colon. Active eosinophils are endowed with bactericidal and T cell regulatory activity, and express the co-stimulatory molecules CD80 and PD-L1. Notably, active eosinophils are enriched in the lamina propria of a small cohort of patients with inflammatory bowel disease, and are closely associated with CD4+ T cells. Our findings provide insights into the biology of eosinophils and highlight the crucial contribution of this cell type to intestinal homeostasis, immune regulation and host defence. Furthermore, we lay a framework for the characterization of eosinophils in human gastrointestinal diseases.

• MeSH
• analýza genové exprese jednotlivých buněk MeSH
• antigeny CD80 metabolismus   MeSH
• eozinofily * klasifikace   cytologie   imunologie   metabolismus   MeSH
• idiopatické střevní záněty imunologie   MeSH
• imunita * MeSH
• interferon gama MeSH
• interleukin 33 MeSH
• kolitida * imunologie   patologie   MeSH
• lidé MeSH
• myši MeSH
• proteom MeSH
• střeva * imunologie   patologie   MeSH
• T-lymfocyty MeSH
• transkriptom MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The homeostasis of the gut epithelium relies upon continuous renewal and proliferation of crypt-resident intestinal epithelial stem cells (IESCs). Wnt/β-catenin signaling is required for IESC maintenance, however, it remains unclear how this pathway selectively governs the identity and proliferative decisions of IESCs. Here, we took advantage of knock-in mice harboring transgenic β-catenin alleles with mutations that specifically impair the recruitment of N- or C-terminal transcriptional co-factors. We show that C-terminally-recruited transcriptional co-factors of β-catenin act as all-or-nothing regulators of Wnt-target gene expression. Blocking their interactions with β-catenin rapidly induces loss of IESCs and intestinal homeostasis. Conversely, N-terminally recruited co-factors fine-tune β-catenin's transcriptional output to ensure proper self-renewal and proliferative behaviour of IESCs. Impairment of N-terminal interactions triggers transient hyperproliferation of IESCs, eventually resulting in exhaustion of the self-renewing stem cell pool. IESC mis-differentiation, accompanied by unfolded protein response stress and immune infiltration, results in a process resembling aberrant "villisation" of intestinal crypts. Our data suggest that IESC-specific Wnt/β-catenin output requires selective modulation of gene expression by transcriptional co-factors.

• MeSH
• algoritmy MeSH
• beta-katenin chemie   metabolismus   MeSH
• buněčná diferenciace MeSH
• chromatin metabolismus   MeSH
• fenotyp MeSH
• genetická transkripce * MeSH
• homeostáza MeSH
• hyperplazie MeSH
• JNK mitogenem aktivované proteinkinasy metabolismus   MeSH
• kmenové buňky metabolismus   MeSH
• messenger RNA genetika   metabolismus   MeSH
• mutace genetika   MeSH
• mutantní proteiny metabolismus   MeSH
• myši MeSH
• organoidy metabolismus   MeSH
• proliferace buněk MeSH
• restrukturace chromatinu MeSH
• sekvence nukleotidů MeSH
• signální transdukce MeSH
• střevní sliznice cytologie   MeSH
• transkripční faktory metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH