MICA and MICB are stress-induced ligands recognized by the activating receptor NKG2D. A microRNA encoded by human cytomegalovirus downregulates MICB expression by targeting a specific site in the ...MICB 3' untranslated region. As this site is conserved among different MICB alleles and a similar site exists in the MICA 3' untranslated region, we speculated that these sites are targeted by cellular microRNAs. Here we identified microRNAs that bound to these MICA and MICB 3' untranslated region sequences and obtained data suggesting that these microRNAs maintain expression of MICA and MICB protein under a certain threshold and facilitate acute upregulation of MICA and MICB during cellular stress. These microRNAs were overexpressed in various tumors and we demonstrate here that they aided tumor avoidance of immune recognition.
Little is known about how interactions of diet, intestinal stem cells (ISCs), and immune cells affect early-stage intestinal tumorigenesis. We show that a high-fat diet (HFD) reduces the expression ...of the major histocompatibility complex class II (MHC class II) genes in intestinal epithelial cells, including ISCs. This decline in epithelial MHC class II expression in a HFD correlates with reduced intestinal microbiome diversity. Microbial community transfer experiments suggest that epithelial MHC class II expression is regulated by intestinal flora. Mechanistically, pattern recognition receptor (PRR) and interferon-gamma (IFNγ) signaling regulates epithelial MHC class II expression. MHC class II-negative (MHC-II−) ISCs exhibit greater tumor-initiating capacity than their MHC class II-positive (MHC-II+) counterparts upon loss of the tumor suppressor Apc coupled with a HFD, suggesting a role for epithelial MHC class II-mediated immune surveillance in suppressing tumorigenesis. ISC-specific genetic ablation of MHC class II increases tumor burden cell autonomously. Thus, HFD perturbs a microbiome-stem cell-immune cell interaction that contributes to tumor initiation in the intestine.
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•HFD dampens MHC class II expression in IECs, including ISCs•HFD perturbs intestinal microbes that correlate with MHC class II expression in ISCs•PRR and IFNγ signaling mediates epithelial MHC class II expression•Loss of MHC class II on premalignant ISCs enhances tumor initiation
The mechanisms that link pro-obesity high-fat diets (HFDs) to increased colon cancer risk are not well understood. Beyaz and colleagues demonstrate that a HFD promotes intestinal tumor initiation by suppressing microbiome-stem cell-immune cell crosstalk that is mediated by MHC class II expression on intestinal stem cells.
Consecutive exposures to different pathogens are highly prevalent and often alter the host immune response. However, it remains unknown how a secondary bacterial infection affects an ongoing adaptive ...immune response elicited against primary invading pathogens. We demonstrated that recruitment of Sca-1+ monocytes into lymphoid organs during Salmonella Typhimurium (STm) infection disrupted pre-existing germinal center (GC) reactions. GC responses induced by influenza, plasmodium, or commensals deteriorated following STm infection. GC disruption was independent of the direct bacterial interactions with B cells and instead was induced through recruitment of CCR2-dependent Sca-1+ monocytes into the lymphoid organs. GC collapse was associated with impaired cellular respiration and was dependent on TNFα and IFNγ, the latter of which was essential for Sca-1+ monocyte differentiation. Monocyte recruitment and GC disruption also occurred during LPS-supplemented vaccination and Listeria monocytogenes infection. Thus, systemic activation of the innate immune response upon severe bacterial infection is induced at the expense of antibody-mediated immunity.
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•Secondary bacterial infections disrupt existing GCs in an indirect manner•GC B cells are unable to shift toward aerobic glycolysis during systemic inflammation•IFNγ-dependent Sca-1+ monocytes are generated during Salmonella and Listeria infections•Sca-1+ monocytes are home to lymphoid organs and drive GC collapse through TNFα functions
Bacterial infections can interfere with the generation of antibody-mediated immunity through inhibition of germinal center formation. Biram et al. demonstrate that secondary infection by S. Typhimurium and systemic inflammation impose a metabolic shift that is not tolerated by germinal center B cells. This process involves the CCR2-dependent recruitment of IFNγ-driven Sca-1+ monocytes into lymphoid organs and TNFα functions.
Genome-wide association studies (GWASs) are a valuable tool for understanding the biology of complex human traits and diseases, but associated variants rarely point directly to causal genes. In the ...present study, we introduce a new method, polygenic priority score (PoPS), that learns trait-relevant gene features, such as cell-type-specific expression, to prioritize genes at GWAS loci. Using a large evaluation set of genes with fine-mapped coding variants, we show that PoPS and the closest gene individually outperform other gene prioritization methods, but observe the best overall performance by combining PoPS with orthogonal methods. Using this combined approach, we prioritize 10,642 unique gene-trait pairs across 113 complex traits and diseases with high precision, finding not only well-established gene-trait relationships but nominating new genes at unresolved loci, such as LGR4 for estimated glomerular filtration rate and CCR7 for deep vein thrombosis. Overall, we demonstrate that PoPS provides a powerful addition to the gene prioritization toolbox.
Glucocorticoid (GC) hormones are an important ingredient of leukemia therapy since they are potent inducers of lymphoid cell apoptosis. However, the development of GC resistance remains an obstacle ...in GC-based treatment. In the present investigation we found that miR-103 is upregulated in GC-sensitive leukemia cells treated by the hormone. Transfection of GC resistant cells with miR-103 sensitized them to GC induced apoptosis (GCIA), while miR-103 sponging of GC sensitive cells rendered them partially resistant. miR-103 reduced the expression of cyclin dependent kinase (CDK2) and its cyclin E1 target, thereby leading to inhibition of cellular proliferation. miR-103 is encoded within the fifth intron of PANK3 gene. We demonstrate that the GC receptor (GR) upregulates miR-103 by direct interaction with GC response element (GRE) in the PANK3 enhancer. Consequently, miR-103 targets the c-Myc activators c-Myb and DVL1, thereby reducing c-Myc expression. Since c-Myc is a transcription factor of the miR-17~92a poly-cistron, all six miRNAs of the latter are also downregulated. Of these, miR-18a and miR-20a are involved in GCIA, as they target GR and BIM, respectively. Consequently, GR and BIM expression are elevated, thus advancing GCIA. Altogether, this study highlights miR-103 as a useful prognostic biomarker and drug for leukemia management in the future.
Colonic homeostasis entails epithelium-lymphocyte cooperation, yet many participants in this process are unknown. We show here that epithelial microRNAs mediate the mucosa-immune system crosstalk ...necessary for mounting protective T helper type 2 (T(H)2) responses. Abolishing the induction of microRNA by gut-specific deletion of Dicer1 (Dicer1(Δgut)), which encodes an enzyme involved in microRNA biogenesis, deprived goblet cells of RELMβ, a key T(H)2 antiparasitic cytokine; this predisposed the host to parasite infection. Infection of Dicer1(Δgut) mice with helminths favored a futile T(H)1 response with hallmarks of inflammatory bowel disease. Interleukin 13 (IL-13) induced the microRNA miR-375, which regulates the expression of TSLP, a T(H)2-facilitating epithelial cytokine; this indicated a T(H)2-amplification loop. We found that miR-375 was required for RELMβ expression in vivo; miR-375-deficient mice had significantly less intestinal RELMβ, which possibly explains the greater susceptibility of Dicer1(Δgut) mice to parasites. Our findings indicate that epithelial microRNAs are key regulators of gut homeostasis and mucosal immunity.
Little is known about how interactions between diet, intestinal stem cells (ISCs) and immune cells impact early stage intestinal tumorigenesis. We show that a high fat diet (HFD) reduces the ...expression of the major histocompatibility complex II (MHC-II) genes in intestinal epithelial cells including ISCs. This decline in epithelial MHC-II expression in a HFD correlates with reduced intestinal microbiome diversity. Microbial community transfer experiments suggest that epithelial MHC-II expression is regulated by intestinal flora. Mechanistically, pattern recognition receptor (PRR) and IFNg signaling regulate epithelial MHC-II expression. MHC-II− ISCs exhibit greater tumor-initiating capacity than their MHC-II+ counterparts upon loss of the tumor suppressor Apc coupled with a HFD, suggesting a role for epithelial MHC-II-mediated immune surveillance in suppressing tumorigenesis. ISC-specific genetic ablation of MHC-II increases tumor burden in a cell autonomous manner. Thus, HFD perturbs a microbiome–stem cell-immune cell interaction that contributes to tumor initiation in the intestine.
The mechanisms that link pro-obesity high fat (HFD) diets to increased colon cancer risk are not well understood. Beyaz and colleagues demonstrate that a HFD promotes intestinal tumor initiation by suppressing a microbiome – stem cell – immune cell crosstalk that is mediated by MHC-II expression on intestinal stem cells.
Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 ...cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including
BEST4
+
enterocytes, microfold-like cells, and
IL13RA2
+
IL11
+
inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express
CD8
and
IL-17
expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and co-regulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.
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