title: Toll-like Receptor 4 Engagement on Dendritic Cells Restrains Phago-Lysosome Fusion and Promotes Cross-Presentation of Antigens.
abstract: The initiation of cytotoxic immune responses by dendritic cells (DCs) requires the presentation of antigenic peptides derived from phagocytosed microbes and infected or dead cells to CD8(+) T cells, a process called cross-presentation. Antigen cross-presentation by non-activated DCs, however, is not sufficient for the effective induction of immune responses. Additionally, DCs need to be activated through innate receptors, like Toll-like receptors (TLRs). During DC maturation, cross-presentation efficiency is first upregulated and then turned off. Here we show that during this transient phase of enhanced cross-presentation, phago-lysosome fusion was blocked by the topological re-organization of lysosomes into perinuclear clusters. LPS-induced lysosomal clustering, inhibition of phago-lysosome fusion and enhanced cross-presentation, all required expression of the GTPase Rab34. We conclude that TLR4 engagement induces a Rab34-dependent re-organization of lysosomal distribution that delays antigen degradation to transiently enhance cross-presentation, thereby optimizing the priming of CD8(+) T cell responses against pathogens.
authors.affiliation: INSERM U932, Institute Curie, 75248 Paris Cedex 05, France.
authors.forename: Andrés
authors.initials: A
authors.lastname: Alloatti
authors.affiliation: INSERM U932, Institute Curie, 75248 Paris Cedex 05, France; Department of Virology, Faculty of Veterinary Sciences, University of Buenos Aires, 1427 Buenos Aires, Argentina.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Kotsias
authors.affiliation: Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Pauwels
authors.affiliation: INSERM U932, Institute Curie, 75248 Paris Cedex 05, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Carpier
authors.affiliation: UMR3215, Institute Curie, 75248 Paris Cedex 05, France.
authors.forename: Mabel
authors.initials: M
authors.lastname: Jouve
authors.affiliation: Department of Medical Protein Research, VIB, 9000 Ghent, Belgium; Department of Biochemistry, Ghent University, 9000 Ghent, Belgium.
authors.forename: Evy
authors.initials: E
authors.lastname: Timmerman
authors.affiliation: INSERM U932, Institute Curie, 75248 Paris Cedex 05, France.
authors.forename: Luigia
authors.initials: L
authors.lastname: Pace
authors.affiliation: INSERM U932, Institute Curie, 75248 Paris Cedex 05, France; CNRS UMR 144, Institute Curie, 75248 Paris Cedex 05, France.
authors.forename: Pablo
authors.initials: P
authors.lastname: Vargas
authors.affiliation: INSERM U932, Institute Curie, 75248 Paris Cedex 05, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Maurin
authors.affiliation: INSERM U932, Institute Curie, 75248 Paris Cedex 05, France.
authors.forename: Ulf
authors.initials: U
authors.lastname: Gehrmann
authors.affiliation: INSERM U932, Institute Curie, 75248 Paris Cedex 05, France.
authors.forename: Leonel
authors.initials: L
authors.lastname: Joannas
authors.affiliation: INSERM U932, Institute Curie, 75248 Paris Cedex 05, France.
authors.forename: Omar I
authors.initials: OI
authors.lastname: Vivar
authors.affiliation: INSERM U932, Institute Curie, 75248 Paris Cedex 05, France.
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Lennon-Duménil
authors.affiliation: INSERM U932, Institute Curie, 75248 Paris Cedex 05, France; Roche SAS, 92650 Boulogne-Billancourt Cedex, France.
authors.forename: Ariel
authors.initials: A
authors.lastname: Savina
authors.affiliation: Department of Medical Protein Research, VIB, 9000 Ghent, Belgium; Department of Biochemistry, Ghent University, 9000 Ghent, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Gevaert
authors.affiliation: Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
authors.affiliation: INSERM U932, Institute Curie, 75248 Paris Cedex 05, France; Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium. Electronic address: eik.hoffmann@irc.vib-ugent.be.
authors.forename: Eik
authors.initials: E
authors.lastname: Hoffmann
authors.affiliation: INSERM U932, Institute Curie, 75248 Paris Cedex 05, France. Electronic address: sebastian.amigorena@curie.fr.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Amigorena
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000941:Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045142:Cross-Priming / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D008247:Lysosomes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010588:Phagosomes / Q000276:immunology; D034741:RNA, Small Interfering; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D014162:Transfection; D020691:rab GTP-Binding Proteins / Q000276:immunology
chemical_list: D000941:Antigens; D034741:RNA, Small Interfering; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C475889:Rab34 protein, mouse; D020691:rab GTP-Binding Proteins
keywords: GTPase Rab34; Toll-like receptor 4; antigen presentation; cross-presentation; dendritic cell; phagocytosis; phagosome maturation