Abstract
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.
MeSH terms
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Animals
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Antibodies, Neutralizing / pharmacology
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / immunology
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Female
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / immunology
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Gene Expression Regulation
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Granulocytes / drug effects
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Granulocytes / immunology
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Granulocytes / parasitology
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Immunity, Mucosal / drug effects*
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Interferon-gamma / genetics
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Interferon-gamma / immunology
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Interleukin-2 / pharmacology
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Interleukin-2 Receptor alpha Subunit / antagonists & inhibitors
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Interleukin-2 Receptor alpha Subunit / genetics
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Interleukin-2 Receptor alpha Subunit / immunology
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Interleukin-6 / genetics
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Interleukin-6 / immunology
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Macrophages / drug effects
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Macrophages / immunology*
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Macrophages / parasitology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Transgenic
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Nematospiroides dubius / drug effects
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Nematospiroides dubius / immunology*
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Parasite Load
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Signal Transduction
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Strongylida Infections / drug therapy
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Strongylida Infections / immunology*
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Strongylida Infections / parasitology
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / parasitology
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Th1 Cells / drug effects
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Th1 Cells / immunology
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Th1 Cells / parasitology
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Th17 Cells / drug effects
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Th17 Cells / immunology
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Th17 Cells / parasitology
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Transcription Factors / genetics
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Transcription Factors / immunology
Substances
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Antibodies, Neutralizing
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DNA-Binding Proteins
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Interleukin-2
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Interleukin-2 Receptor alpha Subunit
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Interleukin-6
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Transcription Factors
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Zfpn1a2 protein, mouse
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interleukin-6, mouse
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Interferon-gamma