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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. and Maizels, R. M. 2016. Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths. Mucosal Immunology 9 (2) , pp. 428-443. 10.1038/mi.2015.73

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QR Microbiology > QR180 Immunology
Publisher: Nature Publishing Group
ISSN: 1933-0219
Funders: Wellcome Trust
Date of First Compliant Deposit: 3 June 2016
Date of Acceptance: 26 June 2015
Last Modified: 03 Jun 2020 16:45
URI: http://orca.cf.ac.uk/id/eprint/91190

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