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

作者：Alloatti Andres; Kotsias Fiorella; Pauwels Anne Marie; Carpier Jean Marie; Jouve Mabel; Timmerman Evy; Pace Luigia; Vargas Pablo; Maurin Mathieu; Gehrmann Ulf; Joannas Leonel; Vivar Omar I; Lennon Dumenil Ana Maria; Savina Ariel; Gevaert Kris; Beyaert Rudi; Hoffmann Eik^*; Amigorena Sebastian

来源：Immunity, 2015, 43(6): 1087-1100.

DOI：10.1016/j.immuni.2015.11.006

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.

• 出版日期2015-12-15