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Phagosome functions and antigen cross presentation in primary dendritic cells

Final Report Summary - DCBIOX (Phagosome functions and antigen cross presentation in primary dendritic cells.)

This project aimed to unravel the intracellular mechanisms of antigen cross presentation in mouse and human dendritic cells. The main aims of the project were 1- To analyze the mechanisms of control of antigen cross presentation and phagocytic functions in DCs, 2- To study the epigenetic programing of cross presentation during the ontogeny of mouse DC subpopulations, and 3- To investigate the regulation of cross presentation in human primary DCs and to develop translational approaches in cancer. The main results obtained include a series of technological advances allowing measuring specific intracellular steps of antigen presentation, such as export to the cytosol or phagosome maturation using organelle cytometry. Using these state-of-the art technologies, we have shown that Sec61 is not directly involved in antigen export to the cytosol during cross presentation. In contrast, we showed that Sec22b is a critical regulator of antigen cross presentation in vivo. Using mice defective for this gene, and for cross presentation, we showed that tumor rejection in response to antiPD-1 treatment in mice requires antigen cross presentation. We also analyzed the mechanisms of TLR4-mediated regulation of antigen cross presentation, showing how LPS inhibits phagosome-lysosome fusion through cytoplasmic re-distribution of lysosomes. Our main contributions to the epigenetic control of DC functions (Aim 2), we showed that Ubc9, the main sumo-ligase, controls inflammation in myeloid cells, mainly through epigenetic silencing of IFNb gene expression. We also showed that epigenetic de-repression of endogenous retroelements and transposons, and more specifically of LINE-1 family members, results in DNA sensing in the cytosol, leading to cGAS sensing and STING activation. This mechanism contributes to IFN-I production during responses to bacteria. Finally, we initiated analyses of DC differentiation and functions in humans. We showed that monocytes can differentiate into 2 main populations closely related to DCs or macrophages. We unraveled the fundamental mechanisms that control these differentiation paths, and analyzed their relative contributions.