The NKp46 Receptor Contributes to NK Cell Lysis of Mononuclear Phagocytes Infected with an Intracellular Bacterium

Abstract

We used human tuberculosis as a model to investigate the role of NK cytotoxic mechanisms in the immune response to intracellular infection. Freshly isolated NK cells and NK cell lines from healthy donors lysed Mycobacterium tuberculosis-infected monocytes to a greater extent than uninfected monocytes. Lysis of infected monocytes was associated with increased expression of mRNA for the NKp46 receptor, but not the NKp44 receptor. Antisera to NKp46 markedly inhibited lysis of infected monocytes. NK cell-mediated lysis was not due to reduced expression of MHC class I molecules on the surface of infected monocytes or to enhanced production of IL-18 or IFN-γ. NK cell lytic activity against M. tuberculosis-infected monocytes and NKp46 mRNA expression were reduced in tuberculosis patients with ineffective immunity to M. tuberculosis compared with findings in healthy donors. These observations suggest that 1) the NKp46 receptor participates in NK cell-mediated lysis of cells infected with an intracellular pathogen, and 2) the reduced functional capacity of NK cells is associated with severe manifestations of infectious disease.

The innate immune response in human tuberculosis

“…This is via recognition of infected macrophages through receptor molecules such as NKp44, NKp46 and NKG2D (Vankayalapati et al ., 2005). NKs can lyse infected macrophages (Vankayalapati et al ., 2002), produce IFN‐γ to further activate macrophages and can also secrete cytokines that expand CD8 +  T cells and NK T cell (NKTs) populations (Vankayalapati and Barnes, 2009). NKTs recognize lipid antigens presented by CD1a molecules and NKT deficiency is associated with the development of active TB (Sutherland et al ., 2009).…”

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

“…5-7 NKp46 is encoded by Ncr1 and associates with the ITAM-containing CD3ζ or FcRγ polypeptides. Several endogenous ligands of NKp46 have been described including the complement factor P, 8 the intracellular filamentous cytoskeletal protein vimentin expressed on the surface of Mycobacterium tuberculosis –infected monocytes, 9 and several viral proteins such as hemagglutinin and hemagglutinin neuraminidases of the influenza, 10,11 Sendai, 12 Newcastle disease, 13 ectromelia and vaccinia viruses. 14 NKp46 was also shown to recognize PfEMP1 of Plasmodium falciparum , 14 an unknown ligand from Fusobacterium nucleatum , 15 adhesins from Candida glabrata .…”

Increased natural cytotoxicity receptor expression and relevant IL‐10 production in NK cells from chronically infected viremic HCV patients

“…During Mycobacterium tuberculosis infection in vitro, NK cells control pathogen replication in monocytes via natural cytotoxicity receptor (NCR) killing [21], and removal of NK cells from the peripheral blood of patients with latent tuberculosis significantly reduces mycobacterium-specific CD8 + CTL function [22]. Similarly, the dysfunction of NK cells observed during HIV-1 infection [23,24] has been recently associated with decreased expression of the major NCR (NKp30, NKp46 and NKp44), with a significant level of peripheral NK cell activation and inefficient lysis of HIVinfected CD4 + T cells [25][26][27][28].…”

“…Given the findings of relevant perturbations of NCR and of their involvement in the immune responses against chronic persistent infections including HIV and Mycobacterium tuberculosis [21][22][23][24][25][26][27][28] as well as the possible posttranscriptional regulation of NCR in the presence of increasing concentrations of TGF-b [38], we tried to determine whether HCV-infected patients show relevant modifications of triggering receptor expression and of NK cell functional derangement during the chronic phase of HCV infection. We report here on the analysis of freshly separated peripheral blood NK cells from HCV-infected patients, showing modified patterns of NCR expression and cytokine production.…”

“…Additional suggestion of the involvement of innate immune mechanism(s) in the establishment of chronic HCV infection derive from the description of NK cell dysfunction (inhibition) following CD16-mediated triggering when CD81 molecules on NK cells are bound to HCV E2 protein [33]. In addition, reduced NK cell triggering mediated by reduced expression of NKG2D ligands (MIC-A and MIC-B) on mature DC (mDC) [34] as well as increased NK cell inhibition through increased CD94/NKG2A expression and TGF-b and IL-10 production [35,36,37] have been suggested to occur during HCV infection.Given the findings of relevant perturbations of NCR and of their involvement in the immune responses against chronic persistent infections including HIV and Mycobacterium tuberculosis [21][22][23][24][25][26][27][28] as well as the possible posttranscriptional regulation of NCR in the presence of increasing concentrations of TGF-b [38], we tried to determine whether HCV-infected patients show relevant modifications of triggering receptor expression and of NK cell functional derangement during the chronic phase of HCV infection. We report here on the analysis of freshly separated peripheral blood NK cells from HCV-infected patients, showing modified patterns of NCR expression and cytokine production.…”