Human Natural Killer Cells Mediate Killing of Intracellular<i>Mycobacterium tuberculosis</i>H37Rv via Granule-Independent Mechanisms

130

We recently reported that dendritic cells (DC) infected with Mycobacterium tuberculosis (Mtb) produce Th1/IFN-γ-inducing cytokines, IFN-αβ and IL-12. In the present article, we show that maturing Mtb-infected DC express high levels of CCR7 and they become responsive to its ligand CCL21. Conversely, CCR5 expression was rapidly lost from the cell surface following Mtb infection. High levels of CCL3 and CCL4 were produced within 8 h after infection, which is likely to account for the observed CCR5 down-modulation on Mtb-infected DC. In addition, Mtb infection stimulated the secretion of CXCL9 and CXCL10. Interestingly, the synthesis of CXCL10 was mainly dependent on the Mtb-induced production of IFN-αβ. Indeed, IFN-αβ neutralization down-regulated CXCL10 expression, whereas the expression of CXCL9 appeared to be unaffected. The chemotactic activity of the Mtb-infected DC supernatants was evaluated by migration assays using activated NK, CD4+, and CD8+ cells that expressed both CCR5 and CXCR3. Mtb-induced expression of CCL3, CCL4, CXCL9, and CXCL10 was involved in the stimulation of NK and T cell migration. In accordance with the data on the IFN-αβ-induced expression of CXCL10, neutralization of IFN-αβ significantly reduced the chemotactic activity of the supernatant from Mtb-infected DC. This indicates that IFN-αβ may modulate the immune response through the expression of CXCL10, which along with CXCL9, CCL3, and CCL4 participates in the recruitment and selective homing of activated/effector cells, which are known to accumulate at the site of Mtb infection and take part in the formation of the granulomas.

Section: Discussionsupporting

confidence: 74%

IFN-αβ Released by Mycobacterium tuberculosis-Infected Human Dendritic Cells Induces the Expression of CXCL10: Selective Recruitment of NK and Activated T Cells

Lande¹,

Giacomini²,

Grassi³

et al. 2003

130

“…However, IFN-␥ was not required for cytotoxicity, which was unaffected by addition of anti-IFN-␥ Abs. Similarly, IFN-␥ does not mediate the capacity of NK cells to kill intracellular M. tuberculosis (23). Although IFN-␥ produced by NK cells in response to M. tuberculosis-infected macrophages does not directly mediate cytotoxicity, it may contribute to immune defenses by favoring the development of a protective type 1 response, as IFN-␥ can enhance the production of both IL-12 and IL-18 in response to M. tuberculosis (29,30).…”

Section: Discussionmentioning

confidence: 99%

“…Denis (21) first showed that freshly isolated NK cells from healthy donors can lyse M. tuberculosis-infected monocytes and reduce the rate of intracellular bacillary growth, but the mechanisms underlying these effects were not investigated. One study found that growth inhibition was mediated by soluble factors produced by NK cells, whereas another suggested that growth inhibition required contact between NK cells and monocytes and was associated with the induction of monocyte apoptosis (22,23).…”

Section: Discussionmentioning

confidence: 99%

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

Vankayalapati

Wizel

Weis

et al. 2002

137

115

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.

“…Most notably, in vitro experiments showed that IL-12 release that is of paramount importance for the development of a protective Th1 response is restricted to M. Tb-infected DC, whereas macrophages preferentially produce TNF-␣, IL-1, and IL-6 (21,22). Similarly, the selective secretion of type I IFN by M. Tb infected human DC will stimulate and recruit NK cells (23,24), which are capable of killing intracellular M. Tb (25)(26)(27). However, these in vitro observations may not reflect the net effect of type I IFNs in vivo, because-at least in mice-type I IFNs aggravate the course of tuberculosis (28) and NK cells are not substantially involved in protection (29).…”

Section: Discussionmentioning

confidence: 99%

Inverse Correlation of Maturity and Antibacterial Activity in Human Dendritic Cells

Buettner

Meinken

Bastian

et al. 2005

Dendritic cells (DCs) are a key part of host defense against microbial pathogens, being part of the innate immune system, but also instructing the adaptive T cell response. This study was designed to evaluate whether human DCs directly contribute to innate immunity by killing intracellular bacteria, using tuberculosis as a model. DCs were detected in bronchoalveolar lavage samples indicating that DCs are available for immediate interaction with Mycobacterium tuberculosis (M. Tb) after inhalation of the pathogen. The phenotype of DC in bronchoalveolar lavage closely resembles monocyte-derived immature DC (iDC) according to the expression of CD1a, CD83, and CCR7. The antimicrobial activity of iDC against intracellular M. Tb inversely correlated with TNF-α-release and was enhanced by treatment with anti-TNF-α Abs. Differentiation of iDC into mature DC by addition of TNF-α or activation via Toll-like receptors further reduced killing of M. Tb. The antibacterial activity against intracellular M. Tb of all DCs was significantly lower than alveolar macrophages. Therefore, the maintenance of a pool of DCs at the site of disease activity in tuberculosis, and the maturation of these DC by TNF-α provides a mechanism by which M. Tb escapes the innate immune system.