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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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 1

The TLR ligand-induced maturation of DCs is impaired by H. pylori infection.

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The TLR ligand-induced maturation of DCs is impaired by H. pylori infect...
(A–C) BM-DCs were infected with H. pylori (Hp) strain PMSS1 at a MOI of 50 and/or treated with 0.5 μg/ml E. coli LPS for 16 hours prior to (A and B) the flow cytometric analysis of CD80, CD86, and CD40 expression and (C) the quantification of IL-12p40, IL-6, and IL-10 secretion by ELISA. Representative FACS plots are shown for CD80 in A, and the average MFI of CD80, CD86, and CD40 expression of all CD11c+ cells is shown in B. (D and E) BM-DCs were infected with H. pylori strain PMSS1 or its isogenic mutant, PMSS1ΔCagE (ΔE), and/or treated with LPS for 16 hours and (D) assessed for CD80 expression and (E) IL-12p40 secretion. (F and G) BM-DCs were infected with H. pylori strain PMSS1 and/or treated with LPS for 16 hours and (F) assessed for CD80 expression and (G) IL-12p40 secretion; bacteria were separated from the cells by a transwell (tw) filter where indicated. (H and I) BM-DCs were infected with H. pylori strain PMSS1 and/or treated with 0.5 μg/ml LPS or 5 μg/ml Pam3Cys (Pam) for 16 hours and assessed for (H) CD80 expression and (I) IL-12p40 secretion. Data are representative of (D–I) at least 3 and (A–C) up to 8 independent experiments and are represented as mean ± SEM of triplicate cultures. P values were calculated using Student’s t test.