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

J Exp Med. 2007 Apr 16;204(4):893-906. doi: 10.1084/jem.20061293. Epub 2007 Mar 26.

Abstract

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/beta 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/beta. 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/beta 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD11c Antigen / metabolism
  • Cell Differentiation
  • DNA, Protozoan / genetics
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Female
  • Interferon-alpha / biosynthesis
  • Interferon-beta / biosynthesis
  • Interleukin-12 / deficiency
  • Interleukin-12 / genetics
  • Interleukin-12 / immunology*
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / immunology*
  • Leishmania donovani / genetics
  • Leishmaniasis, Visceral / immunology*
  • Leishmaniasis, Visceral / metabolism
  • Leishmaniasis, Visceral / parasitology
  • Leishmaniasis, Visceral / pathology
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Knockout
  • Myeloid Cells / cytology
  • Myeloid Cells / immunology*
  • Phenotype
  • Receptor, Interferon alpha-beta / deficiency
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / metabolism
  • Toll-Like Receptor 9 / immunology*

Substances

  • CD11c Antigen
  • DNA, Protozoan
  • Interferon-alpha
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • Receptor, Interferon alpha-beta
  • Interleukin-12
  • Interferon-beta