DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori–specific immune tolerance, and asthma protection
Mathias Oertli, … , Marianne Quiding-Järbrink, Anne Müller
Mathias Oertli, … , Marianne Quiding-Järbrink, Anne Müller
Published February 6, 2012
Citation Information: J Clin Invest. 2012;122(3):1082-1096. https://doi.org/10.1172/JCI61029.
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Research Article

DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori–specific immune tolerance, and asthma protection

Abstract

Persistent colonization with the gastric bacterial pathogen Helicobacter pylori causes gastritis and predisposes infected individuals to gastric cancer. Conversely, it is also linked to protection from allergic, chronic inflammatory, and autoimmune diseases. We demonstrate here that H. pylori inhibits LPS-induced maturation of DCs and reprograms DCs toward a tolerance-promoting phenotype. Our results showed that DCs exposed to H. pylori in vitro or in vivo failed to induce T cell effector functions. Instead, they efficiently induced expression of the forkhead transcription factor FoxP3, the master regulator of Tregs, in naive T cells. Depletion of DCs in mice infected with H. pylori during the neonatal period was sufficient to break H. pylori–specific tolerance. DC depletion resulted in improved control of the infection but also aggravated T cell–driven immunopathology. Consistent with the mouse data, DCs infiltrating the gastric mucosa of human H. pylori carriers exhibited a semimature DC-SIGN+HLA–DRhiCD80loCD86lo phenotype. Mechanistically, the tolerogenic activity of H. pylori–experienced DCs was shown to require IL-18 in vitro and in vivo; DC-derived IL-18 acted directly on T cells to drive their conversion to Tregs. CD4+CD25+ Tregs from infected wild-type mice but not Il18–/– or Il18r1–/– mice prevented airway inflammation and hyperresponsiveness in an experimental model of asthma. Taken together, our results indicate that tolerogenic reprogramming of DCs ensures the persistence of H. pylori and protects against allergic asthma in a process that requires IL-18.

Authors

Mathias Oertli, Malin Sundquist, Iris Hitzler, Daniela B. Engler, Isabelle C. Arnold, Sebastian Reuter, Joachim Maxeiner, Malin Hansson, Christian Taube, Marianne Quiding-Järbrink, Anne Müller

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Figure 2

H. pylori–experienced DCs induce FoxP3 expression in naive T cells.

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H. pylori–experienced DCs induce FoxP3 expression in naive T cells. ...
(A and B) BM-DCs were infected with H. pylori PMSS1 (MOI 50); after 16 hours, bacteria were killed with antibiotics. DCs were cocultured with immunomagnetically isolated, splenic CD4+CD25– T cells for 3 days in the presence of rTGF-β, rIL-2, and anti-CD3ε mAb prior to flow cytometric analysis of CD4, CD25, and FoxP3 expression. (A) Representative plots of the CD4+ gate, (B) along with mean ± SEM of triplicate cocultures. T cells cultured in the absence of DCs served as controls (ctrls). (C and D) BM-DCs were treated as described in A and B and were additionally loaded with 20 μg/ml ovalbumin prior to coculturing with CD4+CD25– OTII T cells in the presence of rTGF-β and rIL-2. (C) Representative CD25 and FoxP3 plots of the CD4+ gate, (D) along with mean ± SEM of triplicates. (E) BM-DCs and T cells were treated as described in A, except that both populations were separated by a transwell filter where indicated. (F) Wild-type, Myd88–/–, and Tlr2–/– BM-DCs were treated as described in A and B. The mean ± SEM of the CD25+FoxP3+ fraction of the CD4+ gate of triplicate cocultures is shown in E and F. (G and H) Immunomagnetically isolated, MLN-derived CD11c+ DCs were treated and cocultured with T cells as described in A and B. (I and J) MLN-derived CD11c+ DCs were treated and cocultured with OTII T cells as described in C and D. (G and I) Representative FACS plots are shown, (H and J) along with mean ± SEM of triplicate cocultures. Numbers indicate the percentage of FoxP3+CD25+ cells. Data are representative of at least 3 and up to 8 experiments.