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Immunity. 2015 Dec 15;43(6):1087-100. doi: 10.1016/j.immuni.2015.11.006.

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

Author information

1
INSERM U932, Institute Curie, 75248 Paris Cedex 05, France.
2
INSERM U932, Institute Curie, 75248 Paris Cedex 05, France; Department of Virology, Faculty of Veterinary Sciences, University of Buenos Aires, 1427 Buenos Aires, Argentina.
3
Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
4
UMR3215, Institute Curie, 75248 Paris Cedex 05, France.
5
Department of Medical Protein Research, VIB, 9000 Ghent, Belgium; Department of Biochemistry, Ghent University, 9000 Ghent, Belgium.
6
INSERM U932, Institute Curie, 75248 Paris Cedex 05, France; CNRS UMR 144, Institute Curie, 75248 Paris Cedex 05, France.
7
INSERM U932, Institute Curie, 75248 Paris Cedex 05, France; Roche SAS, 92650 Boulogne-Billancourt Cedex, France.
8
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.
9
INSERM U932, Institute Curie, 75248 Paris Cedex 05, France. Electronic address: sebastian.amigorena@curie.fr.

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.

KEYWORDS:

GTPase Rab34; Toll-like receptor 4; antigen presentation; cross-presentation; dendritic cell; phagocytosis; phagosome maturation

PMID:
26682983
DOI:
10.1016/j.immuni.2015.11.006
[Indexed for MEDLINE]
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