Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Beyaz, S; Chung, C; Mou, H; Bauer-Rowe, KE; Xifaras, ME; Ergin, I; Dohnalova, L; Biton, M; Shekhar, K; Eskiocak, O; Papciak, K; Ozler, K; Almeqdadi, M; Yueh, B; Fein, M; Annamalai, D; Valle-Encinas, E; Erdemir, A; Dogum, K; Shah, V; Alici-Garipcan, A; Meyer, HV; Özata, DM; Elinav, E; Kucukural, A; Kumar, P; McAleer, JP; Fox, JG; Thaiss, CA; Regev, A; Roper, J; Orkin, SH; Yilmaz, ÖH

Published Date

  • November 4, 2021

Published In

Volume / Issue

  • 28 / 11

Start / End Page

  • 1922 - 1935.e5

PubMed ID

  • 34529935

Pubmed Central ID

  • PMC8650761

Electronic International Standard Serial Number (EISSN)

  • 1875-9777

Digital Object Identifier (DOI)

  • 10.1016/j.stem.2021.08.007

Language

  • eng

Conference Location

  • United States