TLR9-Dependent Activation of Dendritic Cells by DNA from Leishmania major Favors Th1 Cell Development and the Resolution of Lesions
Open Access
- 1 February 2009
- journal article
- Published by The American Association of Immunologists
- Vol. 182 (3), 1386-1396
- https://doi.org/10.4049/jimmunol.182.3.1386
Abstract
In its vertebrate host, Leishmania encounters cells that express TLRs. Using genetically resistant C57BL/6 mice deficient in either TLR2, 4, or 9, we show in this study that only TLR9-deficient mice are more susceptible to infection with Leishmania major. TLR9-deficient mice resolved their lesions and controlled parasites growth with much lower efficiency than wild-type C57BL/6 mice. The absence of TLR9 also transiently inhibited the development of curative Th1 response. In an attempt to analyze the possible basis for such aberrant response in TLR9−/− mice, we have studied the importance of TLR9 for the activation of dendritic cells (DCs) by L. major. Results show that DCs in the draining lymph nodes are activated following infection with L. major. Furthermore, bone marrow-derived DCs as well as DCs freshly isolated from the spleen of C57BL/6 mice can be activated by either heat-killed or live L. major in vitro. In sharp contrast, L. major failed to activate DCs from TLR9−/− mice. Noteworthily, activation of DCs was abolished either following treatment of the parasites with DNase or after acidification of the endosomal compartment of DCs by chloroquine, pinpointing the DNA of L. major as the possible ligand of TLR9 leading to the activation of DCs. Results showed that DNA purified from L. major was indeed capable of activating DCs in a strictly TLR9-dependent manner. Moreover we showed that the L. major DNA-induced TLR9 signaling in DCs condition these cells to promote IFN-γ production by CD4+ T cells.Keywords
This publication has 46 references indexed in Scilit:
- Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptideNature, 2007
- Ligand-induced conformational changes allosterically activate Toll-like receptor 9Nature Immunology, 2007
- NK cell activation in visceral leishmaniasis requires TLR9, myeloid DCs, and IL-12, but is independent of plasmacytoid DCsThe Journal of Experimental Medicine, 2007
- Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll-like receptor 9Proceedings of the National Academy of Sciences, 2007
- Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNANature Immunology, 2005
- High Levels of Susceptibility and T Helper 2 Response in MyD88-Deficient Mice Infected withLeishmania majorAre Interleukin-4 DependentInfection and Immunity, 2003
- MyD88 is essential for clearance of Leishmania major: possible role for lipophosphoglycan and Toll‐like receptor 2 signalingEuropean Journal of Immunology, 2003
- Leishmania lipophosphoglycan (LPG) activates NK cells through toll-like receptor-2Molecular and Biochemical Parasitology, 2003
- Toll-Like Receptor Signaling PathwaysScience, 2003
- Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor.The Journal of Experimental Medicine, 1992