title: Foxp3⁺ regulatory T cells delay expulsion of intestinal nematodes by suppression of IL-9-driven mast cell activation in BALB/c but not in C57BL/6 mice.
abstract: Accumulating evidence suggests that IL-9-mediated immunity plays a fundamental role in control of intestinal nematode infection. Here we report a different impact of Foxp3⁺ regulatory T cells (Treg) in nematode-induced evasion of IL-9-mediated immunity in BALB/c and C57BL/6 mice. Infection with Strongyloides ratti induced Treg expansion with similar kinetics and phenotype in both strains. Strikingly, Treg depletion reduced parasite burden selectively in BALB/c but not in C57BL/6 mice. Treg function was apparent in both strains as Treg depletion increased nematode-specific humoral and cellular Th2 response in BALB/c and C57BL/6 mice to the same extent. Improved resistance in Treg-depleted BALB/c mice was accompanied by increased production of IL-9 and accelerated degranulation of mast cells. In contrast, IL-9 production was not significantly elevated and kinetics of mast cell degranulation were unaffected by Treg depletion in C57BL/6 mice. By in vivo neutralization, we demonstrate that increased IL-9 production during the first days of infection caused accelerated mast cell degranulation and rapid expulsion of S. ratti adults from the small intestine of Treg-depleted BALB/c mice. In genetically mast cell-deficient (Cpa3-Cre) BALB/c mice, Treg depletion still resulted in increased IL-9 production but resistance to S. ratti infection was lost, suggesting that IL-9-driven mast cell activation mediated accelerated expulsion of S. ratti in Treg-depleted BALB/c mice. This IL-9-driven mast cell degranulation is a central mechanism of S. ratti expulsion in both, BALB/c and C57BL/6 mice, because IL-9 injection reduced and IL-9 neutralization increased parasite burden in the presence of Treg in both strains. Therefore our results suggest that Foxp3⁺ Treg suppress sufficient IL-9 production for subsequent mast cell degranulation during S. ratti infection in a non-redundant manner in BALB/c mice, whereas additional regulatory pathways are functional in Treg-depleted C57BL/6 mice.
authors: Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors: Birte
authors: B
authors: Blankenhaus
authors: Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors: Martina
authors: M
authors: Reitz
authors: Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors: Yannick
authors: Y
authors: Brenz
authors: Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors: Marie-Luise
authors: ML
authors: Eschbach
authors: Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors: Wiebke
authors: W
authors: Hartmann
authors: Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors: Irma
authors: I
authors: Haben
authors: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Helmholtz Centre for Infection Research Braunschweig and the Hanover Medical School, Hanover, Germany.
authors: Tim
authors: T
authors: Sparwasser
authors: Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors: Jochen
authors: J
authors: Huehn
authors: Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Charité-Campus Benjamin Franklin, Berlin, Germany.
authors: Anja
authors: A
authors: Kühl
authors: Division for Cellular Immunology, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors: Thorsten B
authors: TB
authors: Feyerabend
authors: Division for Cellular Immunology, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors: Hans-Reimer
authors: HR
authors: Rodewald
authors: Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors: Minka
authors: M
authors: Breloer
mesh_terms: D000818:Animals; D015550:Cell Degranulation / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D051858:Forkhead Transcription Factors / Q000276:immunology*; D016906:Interleukin-9 / Q000096:biosynthesis / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017170:Strongyloides ratti / Q000276:immunology; D013322:Strongyloidiasis / Q000276:immunology* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016906:Interleukin-9