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 7

Treg induction by tolerogenic DCs requires IL-18.

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Treg induction by tolerogenic DCs requires IL-18. (A) Wild-type BM-DCs w...
(A) Wild-type BM-DCs were infected with H. pylori PMSS1 (MOI 50), and IL-18 secretion was assessed by ELISA. (B and C) Wild-type and Il18–/– BM-DCs were infected as described in A, and cocultured at a 1:2 ratio with immunomagnetically isolated, splenic OTII CD4+CD25– T cells for 3 days in the presence of rTGF-β, rIL-2, and anti-CD3ε mAb prior to the flow cytometric analysis of CD4, CD25, and FoxP3 expression. (B) Representative FACS plots of the CD4+ gate are shown, (C) along with mean ± SEM of triplicate cocultures. (D–G) C57BL/6 and BL/6.Il18–/– mice were infected at 7 days (iN) of age with 1 orogastric dose of H. pylori or remained uninfected. Upon sacrifice after 4 weeks after infection, CD11c+ DCs were immunomagnetically isolated from single cell MLN suspensions of individual mice and cocultured for 3 days with splenic CD4+CD25– T cells at a 1:2 ratio in the presence of rIL-2 and anti-CD3ε mAb and (D and E) with or (F and G) without rTGF-β. (D and E) Cocultures were subjected to flow cytometric analysis of CD4, CD25, and FoxP3 expression (representative mice are shown in E, and the quantification of all mice is shown in D) or (F and G) CD4 and IFN-γ or IL-17 expression. Data shown are representative of at least 3 independent (A–C) in vitro and (D–G) in vivo experiments. Horizontal lines represent the median. (B and E) Numbers indicate the percentage of FoxP3+CD25+ cells.