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

Autor: Smith, K A, Filbey, K J, Reynolds, L A, Hewitson, J P, Harcus, Y, Boon, L, Sparwasser, T, Hämmerling, G, Maizels, R M
Přispěvatelé: Twincore Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hanover and the Helmholtz Centre for Infection Research, Hanover, Germany.
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Zdroj: Smith, K A, Filbey, K J, Reynolds, L A, Hewitson, J P, Harcus, Y, Boon, L, Sparwasser, T, Hämmerling, G & Maizels, R M 2016, ' Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths ', Mucosal Immunology, vol. 9, pp. 428–443 . https://doi.org/10.1038/mi.2015.73
Mucosal Immunology
ISSN: 1933-0219
Popis: 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.Mucosal Immunology advance online publication 19 August 2015. doi:10.1038/mi.2015.73.
Databáze: OpenAIRE
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