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

• DOI: 10.1038/mi.2015.73
• Publication Date: 2015-08-19T12:21:05Z
• Authors: K A Smith; K J Filbey; L A Reynolds; J P Hewitson; Y Harcus; L Boon; T Sparwasser; G Hämmerling; R M Maizels
• Keywords: Mice, Transgenic; Article; Parasite Load; Interferon-gamma; Mice; 03 medical and health sciences; 0302 clinical medicine; Animals; Immunity, Mucosal; Mice, Inbred BALB C; Nematospiroides dubius; Interleukin-6; Macrophages; Interleukin-2 Receptor alpha Subunit; Forkhead Transcription Factors; Antibodies, Neutralizing; 3. Good health; DNA-Binding Proteins; Mice, Inbred C57BL; Gene Expression Regulation; QR180; Interleukin-2; Female; Granulocytes; Signal Transduction

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.