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

Smith, K. A. ORCID: https://orcid.org/0000-0001-8150-5702, 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
Additional Information:	This work is licensed under a Creative Commons Attribution 4.0 International License.
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:	06 May 2023 00:35
URI:	https://orca.cardiff.ac.uk/id/eprint/91190

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