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

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)-α/β 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-α/β. 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-γ 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-α/β receptor−/− mice showed only a minor reduction of NK cell IFN-γ expression. This study provides the first direct evidence that mDCs are essential for eliciting NK cell cytotoxicity and IFN-γ release in vivo and demonstrates that TLR9, mDCs, and IL-12 are functionally linked to the activation of NK cells in visceral leishmaniasis.

Analysis of the expression of toll-like receptors 2 and 4 and cytokine production during experimental Leishmania chagasi infection

“…In addition to the involvement of TLR2 and 4 in leishmaniasis, other TLRs, such as TLR3, TLR7 and TLR9, also operate in Leishmania recognition (Flandin et al 2006, Schleicher et al 2007, Paun et al 2011. It was observed that TLR9 activation by Leishmania seems to be crucial in modulating the production of cytokines, such as IL-12 (Schleicher et al 2007). According to these findings, we suggest that other TLRs could be involved in cytokine modulation during infection with L. chagasi.…”

Probing in vivo dendritic cell functions by conditional cell ablation

“…Viruses cDC requirement for LCMV, 35 HSV-1, 36 VSV, 37 influenza, 38 CTL response cDC independence of anti-VSV B and CD4 T-cell response 36,39 Bacteria cDC requirement for anti-Listeria CTL response 11,40 cDC requirement for efficient Mycobacterium tuberculosis CD4 T-cell response 41 cDC requirement for anti-Salmonella response 42,43 cDC independence of UPEC clearance 44 Parasites cDC requirement for anti-Plasmodium 11 and anti-Leishmania response 45,46 Prions cDC requirement for intestinal Scrapie agent neuroinvasion 47 Miscellaneous Tolerance cDC role in Ig complex-mediated priming and tolerization 48,49 cDC independence of peripheral CD4 T-cell tolerization 50 NK responses cDC requirement for NK cell activation by IL-15 trans-presentation 25 NKT responses cDC requirement for glycolipid presentation 51,52 CTL responses cDC requirement for efficient CTL memory generation 27 Respiratory tract cDC requirement for asthma and experimental allergic rhinitis 18,53 Tumor studies cDC requirement for antitumor immunity 52 DC functions by conditional cell ablation A Sapoznikov and S Jung subpopulations and generally provided by non-hematopoietic cells, including stromal and follicular dendritic cells; 58 and (2) the chemokine macrophage migration inhibitory factor (MIF) that controls mature B-and tumor cell survival through triggering of the CD74-CD44 receptor complex. [59][60][61] 70 on pDC.…”

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

“…However, limited information is available regarding the molecular details as to how DCs respond to the intracellular amastigotes. As professional APCs and potential targets for Leishmania infection, DCs play multiple roles in leishmaniasis: updating/transporting parasites (Moll et al, 1995), initiating innate immunity (Schleicher et al, 2007), priming parasitespecific CD4 + and CD8 + T cells, and maintaining T cell memory/activity (Baldwin et al, 2004;Belkaid et al, 2002;Bertholet et al, 2005;Zaph et al, 2004). Recently, DC-based vaccination for the control of L. major-induced cutaneous leishmaniasis has gained special attention (Ramirez-Pineda et al, 2004;Remer et al, 2007).…”