Journal
CELL REPORTS
Volume 40, Issue 7, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2022.111205
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Funding
- France Bioimaging National Infrastructure
- Fondation pour la Recherche Medicale
- INSERM
- Institut Curie, la Ligue contre le Cancer (Equipe Labellisee Ligue)
- Association de Recherche contre le Cancer (ARC)
- European Research Council [ANR-10-INBS-04]
- ARC postdoctoral fellowship [ANR-10-INBS-04]
- Marie Curie Actions from the European Commission
- Vlaams Instituut voor Biotechnologie (VIB) [FDT201805005336]
- Ghent University
- Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO) [EL2014.LNCC/SA, 2013-AdG 340046 DCBIOX, ANR-10-IDEX-0001-02]
- Flemish Government
- National Health and Medical Research Council of Australia [ANR-11-LABX-0043]
- Wellcome Trust
- Medical Research Council
- [39408]
- [G035320N]
- [G044518N]
- [G0G6618N]
- [G0I5722N]
- [BOF09/01M00709]
- [BOF16/MET_V/007]
- [101578/Z/13/Z]
- [MC_UP_1201/26]
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Despite its importance in immune responses, the molecular pathways underlying antigen cross-presentation are not fully understood. This study reveals that membrane repair plays a crucial role in containing antigen export to the cytosol and cross-presentation in conventional dendritic cells (cDCs).
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.
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