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Unité des Réponses Précoces aux Parasites et Immunopathologie, Département de Parasitologie et Mycologie, Institut Pasteur, Paris, France
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-
production by CD4+ T cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a grant from the Indo-French Centre for the Promotion of Advanced Research and the Institut Pasteur. Financial support for the training of F.H.A.F. was provided by the United Nations Children’s Fund (UNICEF), United Nations Development Program, World Bank, and World Health Organization Special Program for Research and Training in Tropical Diseases. F.H.A.F. has also been supported in part by a fellowship from the University of Damascus, Damascus, Syria.
2 Address correspondence and reprint requests to Dr. Noëlle Doyen, Institut Pasteur, Department of Parasitology and Mycology, Unité des Réponses Précoces aux Parasites et immunophysiopathologie, 28 Rue du Docteur Roux, 75015 Paris, France, E-mail address: ndoyen{at}pasteur.fr
3 Abbreviations used in this paper: DC, dendritic cell; BM, bone marrow; BMDC, BM-derived DC; DC1, Th1-inducing DC; HPRT, hypoxanthine phosphoribosyltransferase; mDC, myeloid DC; ODN, oligodeoxynucleotide; pDC, plasmacytoid DC; poly:IC, polyinosinic-polycitidylic acid.
4 The online version of this article contains supplemental material.
This article has been cited by other articles:
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  C. Bogdan and U. Schleicher Comment on "TLR9-Dependent Activation of Dendritic Cells by DNA from Leishmania major Favors Th1 Cell Development and the Resolution of Lesions" J. Immunol., December 1, 2009; 183(11): 6859 - 6859. [Full Text] [PDF]
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N. Doyen Response to Comment on "TLR9-Dependent Activation of Dendritic Cells by DNA from Leishmania major Favors Th1 Cell Development and the Resolution of Lesions" J. Immunol., December 1, 2009; 183(11): 6859 - 6859. [Full Text] [PDF]
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