IL-17A both initiates, via IFNγ suppression, and limits the pulmonary type 2 immune response to nematode infection

Jesuthas Ajendra; Alistair Chenery; James Parkinson; B.H.K Chan; Stella Pearson; Stefano Colombo; Louis Boon; Richard Grencis; Tara Sutherland; Judith Allen

doi:10.1101/827899

IL-17A both initiates, via IFNγ suppression, and limits the pulmonary type 2 immune response to nematode infection

Jesuthas Ajendra, Alistair Chenery, James Parkinson, B.H.K Chan, Stella Pearson, Stefano Colombo, Louis Boon, Richard Grencis, Tara Sutherland^* (Corresponding Author), Judith Allen^* (Corresponding Author)

^*Corresponding author for this work

Medical Sciences

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Abstract

Nippostrongylus brasiliensis is a well-defined model of type-2 immunity but the early lung migrating phase is dominated by innate IL-17A production. In this study, we confirm previous observations that Il17a-KO mice infected with N. brasiliensis exhibit an impaired type-2 immune response. Transcriptional profiling of the lung on day 2 of N. brasiliensis infection revealed an increased Ifn γ signature in Il17a-KO mice confirmed by enhanced IFN γ protein production in lung lymphocyte populations. Depletion of early IFNγ rescued type-2 immune responses in the Il17a-KO mice demonstrating that IL-17A-mediated suppression of IFNγ promotes type-2 immunity. Notably, later in infection, once the type 2 response was established, IL-17A limited the magnitude of the type 2 response. IL-17A regulation of type-2 immunity was lung-specific and infection with Trichuris muris, revealed that IL-17A promotes a type-2 immune response in the lung even when infection is restricted to the intestine. Together our data reveal IL-17A as a major regulator of pulmonary type-2 immunity such that IL-17A supports early development of a protective type-2 response by suppression of IFN γ but subsequently limits excessive type 2 responses. A failure of this feedback loop may contribute to conditions such as severe asthma, characterised by combined elevation of IL-17 and type-2 cytokines.

Original language	English
Pages (from-to)	958–968
Number of pages	11
Journal	Mucosal Immunology
Volume	13
Early online date	7 Jul 2020
DOIs	https://doi.org/10.1101/827899 https://doi.org/10.1038/s41385-020-0318-2
Publication status	Published - Jul 2020

Bibliographical note

We thank the Flow Cytometry, Bioimaging, and Biological Services core facilities at the University of Manchester. This work was supported by the Wellcome Trust
(106898/A/15/Z to JEA and Z10661/Z/18/Z to RG), the Medical Research Council UK (MR/K01207X/2 to JEA), Medical Research Foundation UK joint funding with Asthma UK (MRFAUK-2015-302 to TES). SC was supported by a Wellcome Trust Studentship (103132/Z/13/Z). We thank Kevin Couper for CD45.1 mice.

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Cite this

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title = "IL-17A both initiates, via IFNγ suppression, and limits the pulmonary type 2 immune response to nematode infection",

abstract = "Nippostrongylus brasiliensis is a well-defined model of type-2 immunity but the early lung migrating phase is dominated by innate IL-17A production. In this study, we confirm previous observations that Il17a-KO mice infected with N. brasiliensis exhibit an impaired type-2 immune response. Transcriptional profiling of the lung on day 2 of N. brasiliensis infection revealed an increased Ifn γ signature in Il17a-KO mice confirmed by enhanced IFN γ protein production in lung lymphocyte populations. Depletion of early IFNγ rescued type-2 immune responses in the Il17a-KO mice demonstrating that IL-17A-mediated suppression of IFNγ promotes type-2 immunity. Notably, later in infection, once the type 2 response was established, IL-17A limited the magnitude of the type 2 response. IL-17A regulation of type-2 immunity was lung-specific and infection with Trichuris muris, revealed that IL-17A promotes a type-2 immune response in the lung even when infection is restricted to the intestine. Together our data reveal IL-17A as a major regulator of pulmonary type-2 immunity such that IL-17A supports early development of a protective type-2 response by suppression of IFN γ but subsequently limits excessive type 2 responses. A failure of this feedback loop may contribute to conditions such as severe asthma, characterised by combined elevation of IL-17 and type-2 cytokines.",

author = "Jesuthas Ajendra and Alistair Chenery and James Parkinson and B.H.K Chan and Stella Pearson and Stefano Colombo and Louis Boon and Richard Grencis and Tara Sutherland and Judith Allen",

note = "We thank the Flow Cytometry, Bioimaging, and Biological Services core facilities at the University of Manchester. This work was supported by the Wellcome Trust (106898/A/15/Z to JEA and Z10661/Z/18/Z to RG), the Medical Research Council UK (MR/K01207X/2 to JEA), Medical Research Foundation UK joint funding with Asthma UK (MRFAUK-2015-302 to TES). SC was supported by a Wellcome Trust Studentship (103132/Z/13/Z). We thank Kevin Couper for CD45.1 mice.",

year = "2020",

month = jul,

doi = "10.1101/827899",

language = "English",

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journal = "Mucosal Immunology",

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T1 - IL-17A both initiates, via IFNγ suppression, and limits the pulmonary type 2 immune response to nematode infection

AU - Ajendra, Jesuthas

AU - Chenery, Alistair

AU - Parkinson, James

AU - Chan, B.H.K

AU - Pearson, Stella

AU - Colombo, Stefano

AU - Boon, Louis

AU - Grencis, Richard

AU - Sutherland, Tara

AU - Allen, Judith

N1 - We thank the Flow Cytometry, Bioimaging, and Biological Services core facilities at the University of Manchester. This work was supported by the Wellcome Trust (106898/A/15/Z to JEA and Z10661/Z/18/Z to RG), the Medical Research Council UK (MR/K01207X/2 to JEA), Medical Research Foundation UK joint funding with Asthma UK (MRFAUK-2015-302 to TES). SC was supported by a Wellcome Trust Studentship (103132/Z/13/Z). We thank Kevin Couper for CD45.1 mice.

PY - 2020/7

Y1 - 2020/7

N2 - Nippostrongylus brasiliensis is a well-defined model of type-2 immunity but the early lung migrating phase is dominated by innate IL-17A production. In this study, we confirm previous observations that Il17a-KO mice infected with N. brasiliensis exhibit an impaired type-2 immune response. Transcriptional profiling of the lung on day 2 of N. brasiliensis infection revealed an increased Ifn γ signature in Il17a-KO mice confirmed by enhanced IFN γ protein production in lung lymphocyte populations. Depletion of early IFNγ rescued type-2 immune responses in the Il17a-KO mice demonstrating that IL-17A-mediated suppression of IFNγ promotes type-2 immunity. Notably, later in infection, once the type 2 response was established, IL-17A limited the magnitude of the type 2 response. IL-17A regulation of type-2 immunity was lung-specific and infection with Trichuris muris, revealed that IL-17A promotes a type-2 immune response in the lung even when infection is restricted to the intestine. Together our data reveal IL-17A as a major regulator of pulmonary type-2 immunity such that IL-17A supports early development of a protective type-2 response by suppression of IFN γ but subsequently limits excessive type 2 responses. A failure of this feedback loop may contribute to conditions such as severe asthma, characterised by combined elevation of IL-17 and type-2 cytokines.

AB - Nippostrongylus brasiliensis is a well-defined model of type-2 immunity but the early lung migrating phase is dominated by innate IL-17A production. In this study, we confirm previous observations that Il17a-KO mice infected with N. brasiliensis exhibit an impaired type-2 immune response. Transcriptional profiling of the lung on day 2 of N. brasiliensis infection revealed an increased Ifn γ signature in Il17a-KO mice confirmed by enhanced IFN γ protein production in lung lymphocyte populations. Depletion of early IFNγ rescued type-2 immune responses in the Il17a-KO mice demonstrating that IL-17A-mediated suppression of IFNγ promotes type-2 immunity. Notably, later in infection, once the type 2 response was established, IL-17A limited the magnitude of the type 2 response. IL-17A regulation of type-2 immunity was lung-specific and infection with Trichuris muris, revealed that IL-17A promotes a type-2 immune response in the lung even when infection is restricted to the intestine. Together our data reveal IL-17A as a major regulator of pulmonary type-2 immunity such that IL-17A supports early development of a protective type-2 response by suppression of IFN γ but subsequently limits excessive type 2 responses. A failure of this feedback loop may contribute to conditions such as severe asthma, characterised by combined elevation of IL-17 and type-2 cytokines.

U2 - 10.1101/827899

DO - 10.1101/827899

M3 - Article

SN - 1933-0219

VL - 13

SP - 958

EP - 968

JO - Mucosal Immunology

JF - Mucosal Immunology

ER -

IL-17A both initiates, via IFNγ suppression, and limits the pulmonary type 2 immune response to nematode infection

Abstract

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