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Mucosal Immunol. 2016 Mar;9(2):428-43. doi: 10.1038/mi.2015.73. Epub 2015 Aug 19.

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

Author information

1
Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, UK.
2
Bioceros Holding BV, Utrecht, The Netherlands.
3
TwinCore, Hannover, Germany.
4
Division of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany.

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.

PMID:
26286232
PMCID:
PMC4677460
DOI:
10.1038/mi.2015.73
[Indexed for MEDLINE]
Free PMC Article

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