Toll-like Receptor 4 Engagement on Dendritic Cells Restrains Phago-Lysosome Fusion and Promotes Cross-Presentation of Antigens

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. Fil: Alloatti, Andrés. Inserm; Francia. Institute Curie; Francia Fil: Kotsias, Fiorella. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario; Argentina. Institute Curie; Francia. Inserm; Francia. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento Virologia; Argentina Fil: Pauwels, Anne Marie. University of Ghent; Bélgica Fil: Carpier, Jean Marie. Institute Curie; Francia. Inserm; Francia Fil: Jouve, Mabel. Institute Curie; Francia Fil: Timmerman, Evy. University of Ghent; Bélgica Fil: Pace, Luigia. Institute Curie; Francia. Inserm; Francia Fil: Vargas, Pablo. Institute Curie; Francia. Inserm; Francia. Centre National de la Recherche Scientifique; Francia Fil: Maurin, Mathieu. Institute Curie; Francia. Inserm; Francia Fil: Gehrmann, Ulf. Institute Curie; Francia. Inserm; Francia Fil: Joannas, Leonel. Institute Curie; Francia. Inserm; Francia Fil: Vivar, Omar I.. Institute Curie; Francia. Inserm; Francia Fil: Lennon Duménil, Ana Maria. Institute Curie; Francia. Inserm; Francia Fil: Savina, Ariel. Institute Curie; Francia. Inserm; Francia. Roche SAS; Francia Fil: Gevaert, Kris. University of Ghent; Bélgica Fil: Beyaert, Rudi. University of Ghent; Bélgica Fil: Hoffmann, Eik. Inserm; Francia. Institute Curie; Francia. University of Ghent; Bélgica Fil: Amigorena, Sebastian. Inserm; Francia. Institute Curie; Francia