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Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths

Helminth infection is frequently associated with the expansion of regulatory T cells (Tregs) and suppression of immune responses to bystander antigens. We show that infection of mice with the chronic gastrointestinal helminth Heligmosomoides polygyrus drives rapid polyclonal expansion of Foxp3(+)Hel...

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Autores principales: Smith, K A, Filbey, K J, Reynolds, L A, Hewitson, J P, Harcus, Y, Boon, L, Sparwasser, T, Hämmerling, G, Maizels, R M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677460/
https://www.ncbi.nlm.nih.gov/pubmed/26286232
http://dx.doi.org/10.1038/mi.2015.73
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author Smith, K A
Filbey, K J
Reynolds, L A
Hewitson, J P
Harcus, Y
Boon, L
Sparwasser, T
Hämmerling, G
Maizels, R M
author_facet Smith, K A
Filbey, K J
Reynolds, L A
Hewitson, J P
Harcus, Y
Boon, L
Sparwasser, T
Hämmerling, G
Maizels, R M
author_sort Smith, K A
collection PubMed
description Helminth infection is frequently associated with the expansion of regulatory T cells (Tregs) and suppression of immune responses to bystander antigens. We show that infection of mice with the chronic gastrointestinal helminth Heligmosomoides polygyrus drives rapid polyclonal expansion of Foxp3(+)Helios(+)CD4(+) thymic (t)Tregs in the lamina propria and mesenteric lymph nodes while Foxp3(+)Helios(−)CD4(+) peripheral (p)Treg expand more slowly. Notably, in partially resistant BALB/c mice parasite survival positively correlates with Foxp3(+)Helios(+)CD4(+) tTreg numbers. Boosting of Foxp3(+)Helios(+)CD4(+) tTreg populations by administration of recombinant interleukin-2 (rIL-2):anti-IL-2 (IL-2C) complex increased worm persistence by diminishing type-2 responsiveness in vivo, including suppression of alternatively activated macrophage and granulomatous responses at the sites of infection. IL-2C also increased innate lymphoid cell (ILC) numbers, indicating that Treg functions dominate over ILC effects in this setting. Surprisingly, complete removal of Tregs in transgenic Foxp3-DTR mice also resulted in increased worm burdens, with “immunological chaos” evident in high levels of the pro-inflammatory cytokines IL-6 and interferon-γ. In contrast, worm clearance could be induced by anti-CD25 antibody–mediated partial depletion of early Treg, alongside increased T helper type 2 responses and without incurring pathology. These findings highlight the overarching importance of the early Treg response to infection and the non-linear association between inflammation and the prevailing Treg frequency.
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spelling pubmed-46774602016-03-25 Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths Smith, K A Filbey, K J Reynolds, L A Hewitson, J P Harcus, Y Boon, L Sparwasser, T Hämmerling, G Maizels, R M Mucosal Immunol Article Helminth infection is frequently associated with the expansion of regulatory T cells (Tregs) and suppression of immune responses to bystander antigens. We show that infection of mice with the chronic gastrointestinal helminth Heligmosomoides polygyrus drives rapid polyclonal expansion of Foxp3(+)Helios(+)CD4(+) thymic (t)Tregs in the lamina propria and mesenteric lymph nodes while Foxp3(+)Helios(−)CD4(+) peripheral (p)Treg expand more slowly. Notably, in partially resistant BALB/c mice parasite survival positively correlates with Foxp3(+)Helios(+)CD4(+) tTreg numbers. Boosting of Foxp3(+)Helios(+)CD4(+) tTreg populations by administration of recombinant interleukin-2 (rIL-2):anti-IL-2 (IL-2C) complex increased worm persistence by diminishing type-2 responsiveness in vivo, including suppression of alternatively activated macrophage and granulomatous responses at the sites of infection. IL-2C also increased innate lymphoid cell (ILC) numbers, indicating that Treg functions dominate over ILC effects in this setting. Surprisingly, complete removal of Tregs in transgenic Foxp3-DTR mice also resulted in increased worm burdens, with “immunological chaos” evident in high levels of the pro-inflammatory cytokines IL-6 and interferon-γ. In contrast, worm clearance could be induced by anti-CD25 antibody–mediated partial depletion of early Treg, alongside increased T helper type 2 responses and without incurring pathology. These findings highlight the overarching importance of the early Treg response to infection and the non-linear association between inflammation and the prevailing Treg frequency. Nature Publishing Group 2016-03 2015-08-19 /pmc/articles/PMC4677460/ /pubmed/26286232 http://dx.doi.org/10.1038/mi.2015.73 Text en Copyright © 2016 Society for Mucosal Immunology http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Smith, K A
Filbey, K J
Reynolds, L A
Hewitson, J P
Harcus, Y
Boon, L
Sparwasser, T
Hämmerling, G
Maizels, R M
Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths
title Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths
title_full Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths
title_fullStr Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths
title_full_unstemmed Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths
title_short Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths
title_sort low-level regulatory t-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677460/
https://www.ncbi.nlm.nih.gov/pubmed/26286232
http://dx.doi.org/10.1038/mi.2015.73
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