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 March 1, 2012; First published February 6, 2012
Citation Information: J Clin Invest. 2012;122(3):1082-1096. https://doi.org/10.1172/JCI61029.
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Category: 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 3

H. pylori infection impairs the ability of DCs to activate T cell effector functions.

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H. pylori infection impairs the ability of DCs to activate T cell effec...
(A–C) BM-DCs were infected as described in Figure 2, A and B, and/or loaded with 20 μg/ml ovalbumin prior to coculturing with immunomagnetically isolated, splenic OTII CD4+CD25– T cells for 3 days in the presence of rIL-2. Anti-CD3ε mAb was added where indicated. (A) IFN-γ–producing CD4+ T cells were quantified by intracellular cytokine staining, and (B) IFN-γ secretion into the supernatant was measured by ELISA. (C) Proliferation of parallel cocultures was determined by [3H] thymidine incorporation. T cells cultured without DCs served as controls (–). (D–F) Immunomagnetically isolated, MLN-derived CD11c+ DCs were infected and/or loaded with 20 μg/ml ovalbumin prior to coculturing with CD4+CD25– T cells in the presence of rIL-2 and anti-CD3ε mAb. (D) Representative FACS plots demonstrating intracellular IFN-γ are shown, (E) along with mean ± SEM of triplicate cocultures and (F) IFN-γ secretion into the supernatant as determined by ELISA. Numbers indicate the percentage of IFN-γ+ cells of the CD4+ gate. All data are representative of at least 3 independent experiments.