<italic toggle="yes">Helicobacter pylori</italic> VacA Targets Myeloid Cells in the Gastric Lamina Propria To Promote Peripherally Induced Regulatory T-Cell Differentiation and Persistent Infection

ABSTRACT The gastric bacterium Helicobacter pylori causes a persistent infection that is directly responsible for gastric ulcers and gastric cancer in some patients and protective against allergic and other immunological disorders in others. The two outcomes of the Helicobacter-host interaction can...

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Autores principales:	Aleksandra Altobelli, Michael Bauer, Karelia Velez, Timothy L. Cover, Anne Müller
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	T-cell immunity T cells dendritic cells host-cell interactions immunomodulation mucosal infection Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3fb57795d7984720afe1061a6effba95
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spelling	oai:doaj.org-article:3fb57795d7984720afe1061a6effba952021-11-15T15:55:25Z<italic toggle="yes">Helicobacter pylori</italic> VacA Targets Myeloid Cells in the Gastric Lamina Propria To Promote Peripherally Induced Regulatory T-Cell Differentiation and Persistent Infection10.1128/mBio.00261-192150-7511https://doaj.org/article/3fb57795d7984720afe1061a6effba952019-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00261-19https://doaj.org/toc/2150-7511ABSTRACT The gastric bacterium Helicobacter pylori causes a persistent infection that is directly responsible for gastric ulcers and gastric cancer in some patients and protective against allergic and other immunological disorders in others. The two outcomes of the Helicobacter-host interaction can be modeled in mice that are infected as immunocompetent adults and as neonates, respectively. Here, we have investigated the contribution of the Helicobacter immunomodulator VacA to H. pylori-specific local and systemic immune responses in both models. We found that neonatally infected mice are colonized at higher levels than mice infected as adults and fail to generate effector T-cell responses to the bacteria; rather, T-cell responses in neonatally infected mice are skewed toward Foxp3-positive (Foxp3+) regulatory T cells that are neuropilin negative and express RORγt. We found these peripherally induced regulatory T cells (pTregs) to be enriched, in a VacA-dependent manner, not only in the gastric mucosa but also in the lungs of infected mice. Pulmonary pTreg accumulation was observed in mice that have been infected neonatally with wild-type H. pylori but not in mice that have been infected as adults or mice infected with a VacA null mutant. Finally, we traced VacA to gastric lamina propria myeloid cells and show that it suppressed interleukin-23 (IL-23) expression by dendritic cells and induced IL-10 and TGF-β expression in macrophages. Taken together, the results are consistent with the idea that H. pylori creates a tolerogenic environment through its immunomodulator VacA, which skews T-cell responses toward Tregs, favors H. pylori persistence, and affects immunity at distant sites. IMPORTANCE Helicobacter pylori has coexisted with humans for at least 60.000 years and has evolved persistence strategies that allow it to evade host immunity and colonize its host for life. The VacA protein is expressed by all H. pylori strains and is required for high-level persistent infection in experimental mouse models. Here, we show that VacA targets myeloid cells in the gastric mucosa to create a tolerogenic environment that facilitates regulatory T-cell differentiation, while suppressing effector T-cell priming and functionality. Tregs that are induced in the periphery during H. pylori infection can be found not only in the stomach but also in the lungs of infected mice, where they are likely to affect immune responses to allergens.Aleksandra AltobelliMichael BauerKarelia VelezTimothy L. CoverAnne MüllerAmerican Society for MicrobiologyarticleT-cell immunityT cellsdendritic cellshost-cell interactionsimmunomodulationmucosal infectionMicrobiologyQR1-502ENmBio, Vol 10, Iss 2 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	T-cell immunity T cells dendritic cells host-cell interactions immunomodulation mucosal infection Microbiology QR1-502
spellingShingle	T-cell immunity T cells dendritic cells host-cell interactions immunomodulation mucosal infection Microbiology QR1-502 Aleksandra Altobelli Michael Bauer Karelia Velez Timothy L. Cover Anne Müller <italic toggle="yes">Helicobacter pylori</italic> VacA Targets Myeloid Cells in the Gastric Lamina Propria To Promote Peripherally Induced Regulatory T-Cell Differentiation and Persistent Infection
description	ABSTRACT The gastric bacterium Helicobacter pylori causes a persistent infection that is directly responsible for gastric ulcers and gastric cancer in some patients and protective against allergic and other immunological disorders in others. The two outcomes of the Helicobacter-host interaction can be modeled in mice that are infected as immunocompetent adults and as neonates, respectively. Here, we have investigated the contribution of the Helicobacter immunomodulator VacA to H. pylori-specific local and systemic immune responses in both models. We found that neonatally infected mice are colonized at higher levels than mice infected as adults and fail to generate effector T-cell responses to the bacteria; rather, T-cell responses in neonatally infected mice are skewed toward Foxp3-positive (Foxp3+) regulatory T cells that are neuropilin negative and express RORγt. We found these peripherally induced regulatory T cells (pTregs) to be enriched, in a VacA-dependent manner, not only in the gastric mucosa but also in the lungs of infected mice. Pulmonary pTreg accumulation was observed in mice that have been infected neonatally with wild-type H. pylori but not in mice that have been infected as adults or mice infected with a VacA null mutant. Finally, we traced VacA to gastric lamina propria myeloid cells and show that it suppressed interleukin-23 (IL-23) expression by dendritic cells and induced IL-10 and TGF-β expression in macrophages. Taken together, the results are consistent with the idea that H. pylori creates a tolerogenic environment through its immunomodulator VacA, which skews T-cell responses toward Tregs, favors H. pylori persistence, and affects immunity at distant sites. IMPORTANCE Helicobacter pylori has coexisted with humans for at least 60.000 years and has evolved persistence strategies that allow it to evade host immunity and colonize its host for life. The VacA protein is expressed by all H. pylori strains and is required for high-level persistent infection in experimental mouse models. Here, we show that VacA targets myeloid cells in the gastric mucosa to create a tolerogenic environment that facilitates regulatory T-cell differentiation, while suppressing effector T-cell priming and functionality. Tregs that are induced in the periphery during H. pylori infection can be found not only in the stomach but also in the lungs of infected mice, where they are likely to affect immune responses to allergens.
format	article
author	Aleksandra Altobelli Michael Bauer Karelia Velez Timothy L. Cover Anne Müller
author_facet	Aleksandra Altobelli Michael Bauer Karelia Velez Timothy L. Cover Anne Müller
author_sort	Aleksandra Altobelli
title	<italic toggle="yes">Helicobacter pylori</italic> VacA Targets Myeloid Cells in the Gastric Lamina Propria To Promote Peripherally Induced Regulatory T-Cell Differentiation and Persistent Infection
title_short	<italic toggle="yes">Helicobacter pylori</italic> VacA Targets Myeloid Cells in the Gastric Lamina Propria To Promote Peripherally Induced Regulatory T-Cell Differentiation and Persistent Infection
title_full	<italic toggle="yes">Helicobacter pylori</italic> VacA Targets Myeloid Cells in the Gastric Lamina Propria To Promote Peripherally Induced Regulatory T-Cell Differentiation and Persistent Infection
title_fullStr	<italic toggle="yes">Helicobacter pylori</italic> VacA Targets Myeloid Cells in the Gastric Lamina Propria To Promote Peripherally Induced Regulatory T-Cell Differentiation and Persistent Infection
title_full_unstemmed	<italic toggle="yes">Helicobacter pylori</italic> VacA Targets Myeloid Cells in the Gastric Lamina Propria To Promote Peripherally Induced Regulatory T-Cell Differentiation and Persistent Infection
title_sort	<italic toggle="yes">helicobacter pylori</italic> vaca targets myeloid cells in the gastric lamina propria to promote peripherally induced regulatory t-cell differentiation and persistent infection
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/3fb57795d7984720afe1061a6effba95
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<italic toggle="yes">Helicobacter pylori</italic> VacA Targets Myeloid Cells in the Gastric Lamina Propria To Promote Peripherally Induced Regulatory T-Cell Differentiation and Persistent Infection

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