Abstracts (complete list) - Wissenschaft Online

Ulrike Schleicher, Jan Liese, Claudia Kurzmann, Christian Bogdan
Selective requirement of Toll-like receptor 9 for the activation
of natural killer cells in cutaneous and visceral leishmaniasis
NK cells contribute to the control of intracellular parasites including Leishmania. In vitro
studies suggested that the activation of NK cells depends on their interaction with
plasmacytoid (pDC) or myeloid dendritic cells (mDC) that sense the pathogen and
generate NK cell-stimulatory signals. Here, we investigated the cell types, pattern
recognition receptors and cytokines that are required for NK cell activation during
Leishmania infections in vivo.
Toll-like receptor (TLR) 9 was indispensable for NK cell IFN-gamma production and
cytotoxicity in both cutaneous (L. major) and visceral leishmaniasis (L. infantum). In
vitro, plasmacytoid dendritic cells (pDCs) released both interferon (IFN)-alpha/beta and
interleukin (IL)-12 in response to Leishmania promastigotes in a TLR9-dependent
manner, although they did not internalize the parasites. In contrast, myeloid dendritic
cells (mDCs) phagocytosed the parasites and produced high amounts of IL-12, but not
IFN-alpha/beta, in the presence of TLR9. Studies with IL-12- or IFN-alpha/beta receptor
(IFNAR)-knockout mice revealed that IFNAR-deficiency only slightly reduced the L.
infantum-induced IFN-gamma production by NK cells, whereas NK cell cytotoxicity and
IFN-gamma secretion was abolished in IL-12-deficient mice. The latter phenotype was
also observed in mDC-depleted mice, whereas NK cell activation in response to L.
infantum was maintained after depletion of pDCs. Intracellular cytokine staining showed
that mDCs represent the source of IL-12 during the early phase of Leishmania infection.
TLR9-deficient mice lacked IL-12 expression by mDCs after infection with L. major or L.
infantum. Thus, NK cell priming in vivo in response to Leishmania parasites is strictly
dependent on mDCs, which sense the pathogen via TLR9 and subsequently secrete IL-
12 to stimulate the NK cells.