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. (doi: 10.1038/mi.2015.73) (PMID:26286232) (PMCID:PMC4677460)

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: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Maizels, Professor Rick
• Authors: Smith, K.A., Filbey, K.J., Reynolds, L.A., Hewitson, J.P., Harcus, Y., Boon, L., Sparwasser, T., Hämmerling, G., and Maizels, R.M.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Mucosal Immunology
• Publisher: Nature Publishing Group
• ISSN: 1933-0219
• ISSN (Online): 1935-3456
• Published Online: 19 August 2015
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Mucosal Immunology 9(2): 428-443
• Publisher Policy: Reproduced under a Creative Commons License