Control ofMycobacterium tuberculosisgrowth by activated natural killer cells

Guerra, Carlos; Johal, K; Morris, Devin; Moreno, Sandra; Alvarado, Omar; Gray, Dennis; Tanzil, M; Pearce, Daniel; Venketaraman, Vishwanath

doi:10.1111/j.1365-2249.2011.04552.x

Cited by 70 publications

(95 citation statements)

References 23 publications

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“…Interestingly, it has been reported that NK cells can contribute to immune defence against MTB through the production of IL-22, which inhibits intracellular mycobacterial growth by enhancing phagolysosomal fusion [51]. A role for glutathione, alone and in conjunction with IL-2 and IL-12, in activating the ability of NK cells to control the growth of MTB inside human monocytes has also been demonstrated [52], highlighting that multiple mechanisms might be involved in restricting MTB intracellular growth by human NK cells. …”

Section: Nk Cells and Tb: In Vitro Studiesmentioning

confidence: 99%

Natural Killer Cells: A Coherent Model for Their Functional Role in Mycobacterium tuberculosis Infection

Esin

Batoni

2014

J Innate Immun

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Tuberculosis is still a leading cause of bacterial infection worldwide, with an estimate of over two billion people latently infected with Mycobacterium tuberculosis (MTB). A delicate interplay between MTB and the host's innate and acquired immune system can influence the outcome of the infection, which ranges from pathogen elimination to the establishment of a latent infection or a progressive disease. Although the host cell-mediated adaptive immune response is of vital importance in the control of MTB infection, growing evidence indicates that innate immune cells may greatly influence the outcome of the interaction between the bacterium and the host. Among the cell populations likely to play a role in the host immune response to MTB, natural killer (NK) cells have recently attracted considerable interest. This review is dedicated to dissecting the role of NK cells in immunity to tuberculosis, reporting the most relevant findings and providing a working model of the possible contribution of NK cells in early and late events associated with MTB infection.

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Section: Nk Cells and Tb: In Vitro Studiesmentioning

confidence: 99%

Natural Killer Cells: A Coherent Model for Their Functional Role in Mycobacterium tuberculosis Infection

Esin

Batoni

2014

J Innate Immun

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“…43 Interestingly, Guerra et al demonstrated that IL12-mediated upregulation of FasL and CD40L was involved in the control of mycobacterium tuberculosis growth by activated NK cells. 44 Deficiency in both IL12 and FasL expression can, therefore, contribute to susceptibility to infection. Previous analysis of patients with IL12RB1 mutations demonstrated deficient IL12/JAK/STAT signaling (as could be confirmed for the patient analyzed here), lack of resulting IFNg production by T and NK cells as well as deficient IL23 signaling and low levels of IL17-producing T cells.…”

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confidence: 99%

Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nFor instance, forced expression of the Fas regulating miR146a caused an immune disorder similar to ALPS in transgenic mice. 22 One factor known to regulate expression of both Fas and FasL is interleukin-12 (IL12). [23][24][25][26][27][28][29][30] This cytokine mediates its effects via binding to a heterodimeric receptor composed of the IL12 receptors β1 (IL12RB1) and β2 (IL12RB2) and subsequent activation of JAK/STAT signaling. 31 The IL12 receptor is mainly expressed on T lymphocytes and natural killer (NK) cells. IL12RB1 deficiency is associated with Mendelian susceptibility to mycobacterial diseases. [32][33][34][35] These diseases predispose affected individuals to mycobacterial infections (tuberculosis) due to disturbance of IL12/IL23/IFNg signaling. IL12RB1 also associates with IL23R to form the IL23 receptor. Phagocytic cells release both IL12 and IL23 in response to non-viral infections to induce the secretion of interferon (IFN)g by T and NK cells. This in turn stimulates phagocytes to eliminate intracellular pathogens and activation of IFNg−secreting T helper cells. The IL12 signaling pathway is known to regulate FasL expression on activated T cells and knockout of IL12RB2 predisposes mice to spontaneous autoimmunity, lymphoproliferation and B-cell malignancies. 36 In the present study we identified a patient with a classical ALPS phenotype that was associated with a truncating nonsense mutation in IL12RB1 and loss of IL12/IL23-mediated signaling. Methods Study cohorts and DNA isolationTwenty-six ALPS patients, relatives and healthy controls were enrolled in the study. Written informed consent was obtained from all participants. Experiments were approved by the Ethical Review Boards of Hadassah, the Israeli Ministry of Health and the local Ethics committee of the University of Düsseldorf. Mononuclear cells were derived from peripheral blood by Ficoll (Biochrom, Berlin, Germany) density centrifugation. DNT cells were magnetically selected employing the double-negative T-cell isolation kit (Miltenyi, Bergisch-Gladbach, Germany). Genomic DNA was isolated from whole blood or DNT cells using the DNA blood kit (Qiagen, Hilden, Germany). Whole-exome sequencing and data analysisAfter exclusion of mutations in known ALPS-associated genes by targeted Sanger sequencing (Online Supplementary Methods, Online Supplementary Table S1) whole-exome sequencing was carried out as described elsewhere. 37 In brief, sequencing libraries of 350 bp fragments were generated from sheared genomic DNA. Exome capture was performed using the SeqCap EZ Exome Library 2.0 kit (Roche/Nimblegen, Madison, WI, USA). One hundred base-pair, single-read sequencing was performed on a HiSeq2000 (Illumina, San Diego, CA, USA).Sequencing data were aligned against the human reference genome hg19 (GRCh37, statistics provided in Online Supplementary Table S2) and converted using Samtools. 38 Variation calls were obtained employing GATK, HapMap, OmniArray and dbSNP134 datasets (The Broad Institu...

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“…Moreover, a direct link between NK cells and MTB-infected cells has been shown to be mediated by the interaction of NKp46 and NKG2D activating receptors on NK cells with infected monocytes [14]. Evidence for NK-mediated control of MTB replication is provided by in vitro experiments in which cells from healthy donors promote intracellular killing of mycobacteria [15][16][17] and lyse monocytes infected with MTB, BCG or M. aviumcomplex [18][19][20]. In addition, NK cells from patients with latent TB contribute to adaptive immunity against MTB by enhancing the mycobacteria-specific CD8 + T cell effector functions [4] and by inhibiting expansion of regulatory T cells [21].…”

Section: Introductionmentioning

confidence: 99%

Interaction of Mycobacterium tuberculosis Cell Wall Components with the Human Natural Killer Cell Receptors NKp44 and Toll‐Like Receptor 2

et al. 2013

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We have previously demonstrated that a soluble form of the human NK cell natural cytotoxicity receptor NKp44, binds to the surface of Mycobacterium tuberculosis (MTB). Herein, we investigated the interaction of MTB cell wall components (CWC) with NKp44 or with Toll-like receptor 2 (TLR2) and the role of NKp44 and TLR2 in the direct activation of NK cells upon stimulation with MTB CWC. By using several purified bacterial CWC in an ELISA, we demonstrated that NKp44 was able to bind to the MTB cell wall core mycolyl-arabinogalactan-peptidoglycan (mAGP) as well as to mycolic acids (MA) and arabinogalactan (AG), while soluble TLR2 bound to MTB peptidoglycan (PG), but not to MA or AG. The mAGP complex induced NK cell expression of CD25, CD69, NKp44 and IFN-c production at levels comparable to M. bovis Bacillus Calmette-Gu erin-stimulated (BCG) cells. While AG and MA used alone failed to induce NK cell activation, mycobacterial PG-exhibited NK cell stimulatory capacity. Activation of resting NK cells by mAGP and IFN-c production were inhibited by anti-TLR2 MAb, but not by anti-NKp44 MAb. Differently, anti-NKp44 MAb partially inhibited CD69 expression on NK cells pre-activated with IL-2 and then stimulated with mAGP or whole BCG. Overall, these results provide evidence that components abundant in mycobacterial cell wall are able to interact with NKp44 (AG, MA) and TLR-2 (PG), respectively. While interaction of TLR2 with mycobacterial cell wall promotes activation of resting NK cells and IFN-c production, NKp44 interaction with its putative ligands could play a secondary role in maintaining cell activation.

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Control ofMycobacterium tuberculosisgrowth by activated natural killer cells

Abstract: SummaryWe characterized the underlying mechanisms by which glutathione (

Cited by 70 publications

References 23 publications

Natural Killer Cells: A Coherent Model for Their Functional Role in <b><i>Mycobacterium tuberculosis</i></b> Infection

Natural Killer Cells: A Coherent Model for Their Functional Role in <b><i>Mycobacterium tuberculosis</i></b> Infection

Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease

Interaction of Mycobacterium tuberculosis Cell Wall Components with the Human Natural Killer Cell Receptors NKp44 and Toll‐Like Receptor 2

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