Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis

Publication date: Available online 14 June 2018 Source:Cell Author(s): Paul K. Ziegler, Julia Bollrath, Charles K. Pallangyo, Takaji Matsutani, Özge Canli, Tiago De Oliveira, Michaela A. Diamanti, Nina Müller, Jaba Gamrekelashvili, Tracy Putoczki, David Horst, Arun K. Mankan, Meryem G. Öner, Susanna Müller, Josef Müller-Höcker, Thomas Kirchner, Julia Slotta-Huspenina, M. Mark Taketo, Thomas Reinheckel, Stefan Dröse, Andrew C. Larner, Winfried S. Wels, Matthias Ernst, Tim F. Greten, Melek C. Arkan, Thomas Korn, Dagmar Wirth, Florian R. Greten 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 i...
Source: Cell - Category: Cytology Source Type: research