Dietary suppression of MHC-II expression in intestinal stem cells enhances intestinal tumorigenesis
Abstract Little is known about how interactions between diet, immune recognition, and intestinal stem cells (ISCs) impact the early steps of intestinal tumorigenesis. Here, we show that a high fat diet (HFD) reduces the expression of the major histocompatibility complex II (MHC-II) genes in ISCs. This decline in ISC MHC-II expression in a HFD correlates with an altered intestinal microbiome composition and is recapitulated in antibiotic treated and germ-free mice on a control diet. Mechanistically, pattern recognition receptor and IFNg signaling regulate MHC-II expression in ISCs. Although MHC-II expression on ISCs is dispensable for stem cell function in organoid culturesin vitro, upon loss of the tumor suppressor geneApcin a HFD, MHC-II- ISCs harbor greaterin vivotumor-initiating capacity than their MHC-II+ counterparts, thus implicating a role for epithelial MHC-II in suppressing tumorigenesis. Finally, ISC-specific genetic ablation of MHC-II in engineeredApc-mediated intestinal tumor models increases tumor burden in a cell autonomous manner. These findings highlight how a HFD alters the immune recognition properties of ISCs through the regulation of MHC-II expression in a manner that could contribute to intestinal tumorigenesis..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 07. Okt. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Beyaz, Semir [VerfasserIn] |
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| doi: |
10.1101/2020.09.05.284174 |
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| PPN (Katalog-ID): |
XBI018699669 |
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| 245 | 1 | 0 | |a Dietary suppression of MHC-II expression in intestinal stem cells enhances intestinal tumorigenesis |
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| 520 | |a Abstract Little is known about how interactions between diet, immune recognition, and intestinal stem cells (ISCs) impact the early steps of intestinal tumorigenesis. Here, we show that a high fat diet (HFD) reduces the expression of the major histocompatibility complex II (MHC-II) genes in ISCs. This decline in ISC MHC-II expression in a HFD correlates with an altered intestinal microbiome composition and is recapitulated in antibiotic treated and germ-free mice on a control diet. Mechanistically, pattern recognition receptor and IFNg signaling regulate MHC-II expression in ISCs. Although MHC-II expression on ISCs is dispensable for stem cell function in organoid culturesin vitro, upon loss of the tumor suppressor geneApcin a HFD, MHC-II- ISCs harbor greaterin vivotumor-initiating capacity than their MHC-II+ counterparts, thus implicating a role for epithelial MHC-II in suppressing tumorigenesis. Finally, ISC-specific genetic ablation of MHC-II in engineeredApc-mediated intestinal tumor models increases tumor burden in a cell autonomous manner. These findings highlight how a HFD alters the immune recognition properties of ISCs through the regulation of MHC-II expression in a manner that could contribute to intestinal tumorigenesis. | ||
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| 700 | 1 | |a Xifaras, Michael E. |4 aut | |
| 700 | 1 | |a Ergin, Ilgin |4 aut | |
| 700 | 1 | |a Dohnalova, Lenka |4 aut | |
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| 700 | 1 | |a Shekar, Karthik |4 aut | |
| 700 | 1 | |a Mou, Haiwei |4 aut | |
| 700 | 1 | |a Eskiocak, Onur |4 aut | |
| 700 | 1 | |a Özata, Deniz M. |4 aut | |
| 700 | 1 | |a Papciak, Katherine |4 aut | |
| 700 | 1 | |a Chung, Charlie |4 aut | |
| 700 | 1 | |a Almeqdadi, Mohammed |4 aut | |
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| 700 | 1 | |a Valle-Encinas, Eider |4 aut | |
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| 700 | 1 | |a Elinav, Eran |4 aut | |
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| 700 | 1 | |a Regev, Aviv |4 aut | |
| 700 | 1 | |a Orkin, Stuart H. |4 aut | |
| 700 | 1 | |a Yilmaz, Ömer H. |4 aut | |
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