Endocytic membrane repair by ESCRT-III controls antigen export to the cytosol during antigen cross-presentation

Despite its crucial role in initiation of cytotoxic immune responses, the molecular pathways underlying anti-gen cross-presentation remain incompletely understood. The mechanism of antigen exit from endocytic compartments into the cytosol is a long-standing matter of controversy, confronting two main models: trans-fer through specific channels/transporters or rupture of endocytic membranes and leakage of luminal content. By monitoring the occurrence of intracellular damage in conventional dendritic cells (cDCs), we show that cross-presenting cDC1s display more frequent endomembrane injuries and increased recruitment of endosomal sorting complex required for transport (ESCRT)-III, the main repair system for intracellular membranes, relative to cDC2s. Silencing of CHMP2a or CHMP4b, two effector subunits of ESCRT-III, en-hances cytosolic antigen export and cross-presentation. This phenotype is partially reversed by chemical in-hibition of RIPK3, suggesting that endocytic damage is related to basal activation of the necroptosis pathway. Membrane repair therefore proves crucial in containing antigen export to the cytosol and cross -pre-sentation in cDCs.