Browsing by keyword "MHC-II"
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Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesisLittle 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 (IFNgamma) 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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The non-classical MHC-II molecule DO regulates diversity of the immunopeptidome and selection of the CD4 regulatory T cell lineagePresentation of antigenic peptides on MHC-II molecules is essential for induction of tolerance to self and for effective immunity against foreign pathogens. The non- classical MHC-II molecule DO (HLA-DO in humans, H2-O in mice) functions in selection of MHC-II epitopes by competitively inhibiting the peptide exchange factor DM. Previous studies have suggested a role for DO in development of autoimmunity and in the immune response to retroviral infection, presumably via modulation of the MHC-II peptidome, but the precise effect of DO has been difficult to discern. Through characterization of the full spectrum of peptides from DO-sufficient and DO-deficient cells, we demonstrate that DO functions to broaden the diversity of peptide species presented on MHC-II. DO is regulated differently from other components of the MHC-II processing machinery, with expression limited to B cell and dendritic cell subsets, as well as thymic epithelial cells, suggesting a role for DO in mediating central tolerance. In a mouse model lacking DO, we show that selection of T regulatory cells (Tregs) is increased and that DO- deficient Tregs are more activated and exert greater suppressive capacity. Despite augmented Treg function, mice lacking DO display enhanced susceptibility to autoimmunity, with altered germinal center (GC) Tregs and B cells indicative of an aberrant GC reaction. These data suggest that DO expression serves to fine-tune the immunopeptidome in order to promote self-tolerance to a wide spectrum of epitopes and to select a Treg population with appropriate specificity for self- antigens.
