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

Abstract

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.

Klebsiella pneumoniae‐triggered DC recruit human NK cells in a CCR5‐dependent manner leading to increased CCL19‐responsiveness and activation of NK cells

“…It can be hypothesized that chemokines produced by DC, triggered with bacterial fragments, are responsible for NK-cell recruitment to inflamed tissue and into the inflammatory lymph node. The ability of human DC to recruit NK cells is consistent with the previous studies that report on CCL5 and CXCL10 production and NK-cell recruitment by DC either infected with Mycobacterium tuberculosis [30], stimulated by oncolytic reovirusus [31] or matured with IFN-a/IFN-g/TNF-a/IL-1b/poly-(I:C). Blocking of CXCR3 did not affect NK-cell migration to IFN-g/FMKp-matured DC; therefore, our data suggest that CXCR3-and CCR5-dependent NK-cell recruitments are two different mechanisms by which NK cells can be attracted by DC.…”

BCG Vaccination Induces Robust CD4+ T Cell Responses to Mycobacterium tuberculosis Complex–Specific Lipopeptides in Guinea Pigs

“…The secretion of conserved, highly immunogenic lipopeptides may be part of this mycobacterial strategy. Lipopeptide-reactive T cells, as described in TB-infected humans, secrete high amounts of IFN-g, TNF-a, RANTES, and CCL-3, factors involved in granuloma formation (47,48). In addition, they express antimicrobial effector molecules, such as perforin and granulysin, and kill intracellular mycobacteria (22), suggesting that they are able to identify and eliminate mycobacteria in peripheral tissues.…”

Mycobacterial Lipopeptides Elicit CD4+ CTLs in Mycobacterium tuberculosis-Infected Humans

“…In infected tissue, lipopeptidereactive cells could contribute to elimination of pathogens by the release of Th1 cytokines and chemokines crucial for granuloma formation and containment of M.Tb (97,98). Notably, M.Tb-expanded T lymphocytes secreted significant levels of the Th1-associated chemokines CCL5 and CCL3 (99, 100) even without Agspecific restimulation (Fig.…”