%0 Journal Article
%1 smithlowlevel
%A Smith, K A
%A Filbey, K J
%A Reynolds, L A
%A Hewitson, J P
%A Harcus, Y
%A Boon, L
%A Sparwasser, T
%A Hammerling, G
%A Maizels, R M
%D 2016
%E Immunol, Mucosal
%J Mucosal Immunol
%K sparwasser
%N 2
%P 428-443
%T Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths
%V 9
%X 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 ldquoimmunological chaosrdquo evident in high levels of the pro-inflammatory cytokines IL-6 and interferon-gamma. 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.