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 5

H. pylori–exposed DCs exhibit tolerogenic properties and are required for tolerance in vivo.

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H. pylori–exposed DCs exhibit tolerogenic properties and are required f...
(A–E) C57BL/6 mice were infected with H. pylori at 7 days (iN) or 6 weeks (iA) of age. Upon sacrifice, CD11c+ MLN-DCs were immunomagnetically isolated; cocultured for 3 days with splenic CD4+CD25– T cells, rTGF-β, rIL-2, and anti-CD3ε mAb; and subjected to flow cytometric analysis of CD4, CD25, and FoxP3 expression. (A) CD25 and FoxP3 staining of the CD4+ gate is shown for representative donors and (B) quantified for all donors. Numbers indicate the percentage of FoxP3+CD25+ cells. (C) H. pylori colonization of mice analyzed in B. (D) CD4+ T cell infiltration into the gastric mucosa of mice shown in B and C. (E) DCs prepared, as described in A, were cultured with CD4+CD25– T cells, rIL-2, and anti-CD3ε mAb and subjected to intracellular IFN-γ staining. Each symbol represents an individual donor, and data are pooled from 2 experiments in B–E. (F–L) cd11c-DTR tg mice and their wild-type littermates were infected at 1 week of age with H. pylori strain PMSS1 or remained uninfected. (F) All mice received diphtheria toxin during the final 2 weeks of the experiment and were sacrificed 8 weeks after infection. (G) Gastric H. pylori colonization. (H and I) Gastric CD45+ leukocyte and CD4+ T cell infiltration. (J) Intracellular IFN-γ expression by gastric CD4+ T cells. (K and L) Gastric histopathology, as assessed on Giemsa-stained sections. Representative micrographs are shown in L. Original magnification, ×100 (top); ×200 (bottom). Inflammation scores are shown in K. Data in F–L are pooled from 3 experiments. Horizontal lines indicate the medians.