Mycobacteria Induce IFN-γ Production in Human Dendritic Cells via Triggering of TLR2

Abstract

IFN-γ is of central importance for the induction of robust cell-mediated immunity and for the activation of APC. Recent studies using experimental murine systems have now suggested a fundamental role for APC-derived IFN-γ during infection with intracellular pathogens. It is currently unknown whether human dendritic cells (DC) can respond to bacterial stimulation with production of IFN-γ. To test this question, we used human monocyte-derived DC stimulated by Mycobacterium bovis bacillus Calmette-Guérin as a model system. We demonstrate production of IFN-γ mRNA and protein on the single cell level. IFN-γ in DC cultures was not simply produced by contaminating lymphocytes because production of DC-IFN-γ could also be demonstrated in highly purified DC cultures containing virtually no T, B, and NK cells. TLR2 was identified as a key receptor involved in triggering production of DC-IFN-γ. Interestingly, DC-IFN-γ seems to participate in an autocrine DC activation loop, and production of DC-IFN-γ could be enhanced by costimulation of DC with IL-12/IL-15/IL-18. In conclusion, we have demonstrated production of IFN-γ by human DC on the single cell level, identified TLR2 as a pattern recognition receptor involved in this process, and elucidated some of the functional consequences of autocrine IFN-γ production by human DC.

Double-Stranded RNA Analog Poly(I:C) Inhibits Human Immunodeficiency Virus Amplification in Dendritic Cells via Type I Interferon-Mediated Activation of APOBEC3G

“…It is unlikely that the IFN-␥ secretion was due to contaminating T cells since there was Ͻ0.9% T cells in these cultures. IFN-␥ production by DCs has been detected in response to intracellular pathogens and certain cytokines (24,25,27). The early (IFN-␥ and TNF-␣) and later, more-potent (IL-12 p70, IFN-␥, and TNF-␣) responses induced by poly(I:C) might contribute to the more effective DC maturation (7,36,46,62), resulting in efficient inhibition of infection.…”

Failure of mycoplasma lipoprotein MALP-2 to induce NK cell activation through dendritic cell TLR2

“…To investigate whether the mycoplasma lipopeptides harbor activity of NK cell activation, we added the Pam2Cys peptides (100 nM) to BMDC, NK cells or BMDC/NK co-culture as in a previous method assessing polyI:C activity for BMDC-mediated NK activation (10). Although BMDC per se can induce IFN-γ production in response to some TLR stimuli (17,18), we could detect only minure amounts of IFN-γ in our setting using Pam2 lipopeptides ( Fig. 2A).…”

Interleukin-18 directly activates T-bet expression and function via p38 mitogen-activated protein kinase and nuclear factor-κB in acute myeloid leukemia–derived predendritic KG-1 cells

“…A prominent function of IL-18 is its crucial role as an efficient costimulus for IFNg production, particularly in synergism with IL-12 or T cell receptor stimulation. Besides T cells and natural killer cells, human dendritic cells (DC) are also capable of potently releasing IFNg under the influence of IL-18 (3,10). IL-18 biological activity seems to be controlled by an IFNginduced negative feedback loop mediated by the IL-18 opponent IL-18 -binding protein (11).…”