Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths.
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.
Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, UK.
K A
KA
Smith
Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, UK.
K J
KJ
Filbey
Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, UK.
L A
LA
Reynolds
Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, UK.
J P
JP
Hewitson
Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, UK.
Y
Y
Harcus
Bioceros Holding BV, Utrecht, The Netherlands.
L
L
Boon
TwinCore, Hannover, Germany.
T
T
Sparwasser
Division of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany.
G
G
Hämmerling
Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, UK.
R M
RM
Maizels
D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D018928:Immunity, Mucosal / Q000187:drug effects*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009351:Nematospiroides dubius / Q000187:drug effects / Q000276:immunology*; D059208:Parasite Load; D015398:Signal Transduction; D017206:Strongylida Infections / Q000188:drug therapy / Q000276:immunology* / Q000469:parasitology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000469:parasitology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology
D057134:Antibodies, Neutralizing; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D014157:Transcription Factors; C491746:Zfpn1a2 protein, mouse; C577686:interleukin-6, mouse; D007371:Interferon-gamma