The Journal of Experimental Medicine
StemCell Technologies
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Published online March 26, 2007
doi:10.1084/jem.20061293
The Journal of Experimental Medicine, Vol. 204, No. 4, 893-906
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Schleicher et al.
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ARTICLE

 NK cell activation in visceral leishmaniasis requires TLR9, myeloid DCs, and IL-12, but is independent of plasmacytoid DCs

Ulrike Schleicher1,2, Jan Liese1, Ilka Knippertz2, Claudia Kurzmann1, Andrea Hesse1,2, Antje Heit3, Jens A.A. Fischer4, Siegfried Weiss5, Ulrich Kalinke6, Stefanie Kunz1, and Christian Bogdan1,2

1 Institute of Medical Microbiology and Hygiene, University of Freiburg, D-79104 Freiburg, Germany
2 Institute of Clinical Microbiology, Immunology and Hygiene, University of Erlangen, 91054 Erlangen, Germany
3 Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, 81675 München, Germany
4 Department of Research and Development, Miltenyi Biotec GmbH, 51429 Bergisch-Gladbach, Germany
5 Department of Molecular Immunology, Helmholtz Zentrum für Infektionsforschung, D-38124 Braunschweig, Germany
6 Department of Immunology, Paul Ehrlich Institute, 63225 Langen, Germany

CORRESPONDENCE Christian Bogdan: christian.bogdan{at}uniklinik-freiburg.de

Natural killer (NK) cells are sentinel components of the innate response to pathogens, but the cell types, pathogen recognition receptors, and cytokines required for their activation in vivo are poorly defined. Here, we investigated the role of plasmacytoid dendritic cells (pDCs), myeloid DCs (mDCs), Toll-like receptors (TLRs), and of NK cell stimulatory cytokines for the induction of an NK cell response to the protozoan parasite Leishmania infantum. In vitro, pDCs did not endocytose Leishmania promastigotes but nevertheless released interferon (IFN)-{alpha}/ß and interleukin (IL)-12 in a TLR9-dependent manner. mDCs rapidly internalized Leishmania and, in the presence of TLR9, produced IL-12, but not IFN-{alpha}/ß. Depletion of pDCs did not impair the activation of NK cells in L. infantum–infected mice. In contrast, L. infantum–induced NK cell cytotoxicity and IFN-{gamma} production were abolished in mDC-depleted mice. The same phenotype was observed in TLR9–/– mice, which lacked IL-12 expression by mDCs, and in IL-12–/– mice, whereas IFN-{alpha}/ß receptor–/– mice showed only a minor reduction of NK cell IFN-{gamma} expression. This study provides the first direct evidence that mDCs are essential for eliciting NK cell cytotoxicity and IFN-{gamma} release in vivo and demonstrates that TLR9, mDCs, and IL-12 are functionally linked to the activation of NK cells in visceral leishmaniasis.

Abbreviations used: BM-mDC, BM-derived myeloid DC; BM-M{Phi}, BM-derived macrophages; BM-pDC, BM-derived plasmacytoid DC; DT, diphtheria toxin; DTR, DT receptor; Flt3L, fms-like tyrosine kinase 3 ligand; gDNA, genomic DNA; GU, guanosine-uridine; IRF, IFN regulatory factor; IFNAR, IFN-{alpha}/ß receptor; kDNA, kinetoplast DNA; mDC, myeloid DC; MM, metallophilic macrophage; MOI, multiplicity of infection; MyD88, myeloid differentiation factor 88; MZM, marginal zone macrophage; ODN, oligodeoxynucleotide; pDC, plasmacytoid DC; ssRNA, single-stranded RNA; TLR, Toll-like receptor.

I. Knippertz and A. Hesse's present address is University Clinic for Dermatology, University of Erlangen, D-91052 Erlangen, Germany.


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