Mycobacteria induce IFN-gamma production in human dendritic cells via triggering of TLR2.
IFN-gamma 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-gamma during infection with intracellular pathogens. It is currently unknown whether human dendritic cells (DC) can respond to bacterial stimulation with production of IFN-gamma. 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-gamma mRNA and protein on the single cell level. IFN-gamma in DC cultures was not simply produced by contaminating lymphocytes because production of DC-IFN-gamma 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-gamma. Interestingly, DC-IFN-gamma seems to participate in an autocrine DC activation loop, and production of DC-IFN-gamma could be enhanced by costimulation of DC with IL-12/IL-15/IL-18. In conclusion, we have demonstrated production of IFN-gamma 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-gamma production by human DC.
Fricke
Ingo
I
Division of Immunotherapy, Research Center Borstel, Parkallee 1-40, 23845 Borstel, Germany.
Mitchell
Daniell
D
Mittelstädt
Jessica
J
Lehan
Nadine
N
Heine
Holger
H
Goldmann
Torsten
T
Böhle
Andreas
A
Brandau
Sven
S
D000818:Animals; D019898:Autocrine Communication; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D007378:Interleukins / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D007378:Interleukins; D051195:Toll-Like Receptor 2; D007371:Interferon-gamma