Under the supervision of Béatrice Romagnolo, team Intestinal self-renewal and tumorigenesis
Autophagy is a catabolic degradation mechanism, shared by all cells, that allows the capture of intracellular compounds and their degradation by the lysosome. Our team has demonstrated the role of autophagy in the intestinal epithelium in managing intestinal stem cells (ISC) stress and survival, as well as in controlling tumor development by establishing an immunosurveillance during colorectal cancer (CRC). Furthermore, alteration of autophagy has been frequently reported in the literature in inflammatory bowel diseases patients. Therefore, a better understanding of how autophagy in the intestinal epithelium regulates immunity could help us to better understand these pathologies. Using a mice model that allows the deletion of the Atg7 gene in the intestine, we have characterized the role of autophagy in the epithelial cells in the control of the immune response by analyzing its effect during bacterial infection, on the ISC niche and on the tumor immune microenvironment. First, we demonstrated that mice lacking autophagy in the intestinal epithelial cells are resistant to Citrobacter rodentium, a pathogen which is commonly used to model human infection of Escherichia coli. We observed that the loss of Atg7 in intestine limits the inflammation and the hyperplasia mediated by C. rodentium. We observed that the inhibition of autophagy reduced T CD4+ lymphocyte recruitment and set up a TH17/Treg immune response via a microbiota-dependent mechanism. Our works also highlight the specificity of the microbiota of Atg7 deficient mice and its anti-inflammatory properties, probably thanks to the abundance of Clostridium cluster IV. Secondly, we showed that autophagy contributes to the MHC-II expression by ISC. Blocking autophagy reduced MHC-II surface expression in ISC and was associated with changes in the immunological niche. These changes were characterized by a decrease in the number of T CD4+ lymphocytes in the vicinity of ISC and by an increase in the proportion of Treg in contact with them. In addition, using an MHC-II deficient mice model, we have identified several modifications of the intestinal epithelium in Atg7 deficient mice that can be attributed to the loss of MHC-II in the ISC. Finally, in a tumoral context mediated by the loss of Apc, we demonstrated that inhibition of autophagy, following the deletion of Atg7, allows the re-expression of MHC-I in intestinal tumors and the presence of an intratumoral immune infiltration, in particular T CD8+ lymphocytes, which have been shown to reduced CRC development. Taken together, this work highlights the importance of autophagy in the dialogue between intestinal epithelial cells and the immune system. This study also highlights the potential positive therapeutic effect of autophagy inhibition on the immune response in various pathological contexts.
Keywords: Autophagy, intestine, MCH, intestinal stem cell, colorectal cancer, Citrobacter rodentium, immunity, microbiota