Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis
Autor: | Julia Bollrath, Charles K. Pallangyo, Tiago De Oliveira, Melek C. Arkan, Takaji Matsutani, David Horst, Jaba Gamrekelashvili, Meryem Gülfem Öner, Özge Canli, Makoto Mark Taketo, Arun K. Mankan, Andrew C. Larner, Paul K. Ziegler, Thomas Reinheckel, Susanna Müller, Nina Müller, Dagmar Wirth, Tracy L Putoczki, Julia Slotta-Huspenina, Thomas Kirchner, Matthias Ernst, Florian R. Greten, Winfried S. Wels, Josef Müller-Höcker, Stefan Dröse, Michaela A. Diamanti, Thomas Korn, Tim F. Greten |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Male STAT3 Transcription Factor Cell Membrane Permeability T cell Azoxymethane Adaptive Immunity CD8-Positive T-Lymphocytes General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Interferon-gamma Mice 0302 clinical medicine Intestinal mucosa MHC class I Mitophagy medicine Cytotoxic T cell Animals Humans Ferrous Compounds Intestinal Mucosa Mice Knockout biology Antigen processing Dendritic Cells Acquired immune system Cell biology Survival Rate 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis biology.protein Cytokines Female Colorectal Neoplasms Lysosomes CD8 |
Zdroj: | Cell. 174(1) |
ISSN: | 1097-4172 |
Popis: | In colorectal cancer patients, a high density of cytotoxic CD8+ T cells in tumors is associated with better prognosis. Using a Stat3 loss-of-function approach in two wnt/β-catenin-dependent autochthonous models of sporadic intestinal tumorigenesis, we unravel a complex intracellular process in intestinal epithelial cells (IECs) that controls the induction of a CD8+ T cell based adaptive immune response. Elevated mitophagy in IECs causes iron(II)-accumulation in epithelial lysosomes, in turn, triggering lysosomal membrane permeabilization. Subsequent release of proteases into the cytoplasm augments MHC class I presentation and activation of CD8+ T cells via cross-dressing of dendritic cells. Thus, our findings highlight a so-far-unrecognized link between mitochondrial function, lysosomal integrity, and MHC class I presentation in IECs and suggest that therapies triggering mitophagy or inducing LMP in IECs may prove successful in shifting the balance toward anti-tumor immunity in colorectal cancer. |
Databáze: | OpenAIRE |
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