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

Immunity. 2015 Dec 15;43(6):1087-100. 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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / immunology*
  • Antigens / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cross-Priming / immunology*
  • Cytotoxicity, Immunologic / immunology
  • Dendritic Cells / immunology*
  • Female
  • Flow Cytometry
  • Lysosomes / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phagosomes / immunology
  • RNA, Small Interfering
  • Toll-Like Receptor 4 / immunology*
  • Transfection
  • rab GTP-Binding Proteins / immunology


  • Antigens
  • RNA, Small Interfering
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Rab34 protein, mouse
  • rab GTP-Binding Proteins