Abstracts (complete list) - Wissenschaft Online

Isabel Koch, Reinhard Hoffmann
Yersinia virulence protein YopP inhibits NK cell cytokine
production by blocking host cell IL-12 signaling.
Yersinia enterocolitica causes acute gastrointestinal disease and evades the host´s
immune response by injecting, via a type III protein secretion system, anti host effector
proteins into the host cell’s cytoplasm. These effector proteins (Yersinia outer proteins,
Yops) interfere with host cell signal transduction; in particular, YopP inhibits NFκB and
MAPK pathways.
NK cells are an important early source of IFN-γ before the onset of adaptive immunity.
To evaluate whether Y. enterocolitica could directly modulate NK cell function, we
isolated 2B4 positive NK cells from spleens of C57BL/6 mice, infected them with highly
virulent Y. enterocolitica in vitro, and evaluated NK cell IFN-γ production. Infection with
wild-type Y. enterocolitica (translocating all six Yop effector proteins) markedly reduced
IFN-γ production induced by IL-12, IL-12+IL-18, and agonistic α-NKG2D antibody in
both naïve and IL-2 stimulatied NK cells. Evaluation of mutant Yersinia strains identified
YopP as an important mediator of NK cell disarmament: YopP not only inhibited
phosphorylation of p38 in response to stimulation with IL-12+IL-18, but also in
response to IL-12 alone. Strikingly, YopP, which has not previously been shown to
interfere with JAK-STAT signal transduction, inhibits tyrosine phosphorylation of STAT-4
in response to IL-12 or IL-12+IL-18 stimulation.
To demonstrate the relevance of these results in vivo, we isolated NK cells from mice
infected with wild-type or YopP deficient Y. enterocolitica. We could show that NK cells
from wild-type infected mice produce lower amounts of IFN-γ protein after restimulation
with IL-12+IL-18. To the best of our knowledge, this is the first report of a
bacterial pathogen directly targeting NK cells for the suppression of an effective immune
response.