ILC3s control airway inflammation by limiting T cell responses to allergens and microbes

Fei Teng; Roser Tachó-Piñot; Biin Sung; Donna L. Farber; Stefan Worgall; Hamida Hammad; Bart N. Lambrecht; Matthew R. Hepworth; Gregory F. Sonnenberg

doi:10.1016/j.celrep.2021.110051

ILC3s control airway inflammation by limiting T cell responses to allergens and microbes

Fei Teng, Roser Tachó-Piñot, Biin Sung, Donna L. Farber, Stefan Worgall, Hamida Hammad, Bart N. Lambrecht, Matthew R. Hepworth^*, Gregory F. Sonnenberg

^*Corresponding author for this work

Pulmonary Medicine

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Group 3 innate lymphoid cells (ILC3s) critically regulate host-microbe interactions in the gastrointestinal tract, but their role in the airway remains poorly understood. Here, we demonstrate that lymphoid-tissue-inducer (LTi)-like ILC3s are enriched in the lung-draining lymph nodes of healthy mice and humans. These ILC3s abundantly express major histocompatibility complex class II (MHC class II) and functionally restrict the expansion of allergen-specific CD4⁺ T cells upon experimental airway challenge. In a mouse model of house-dust-mite-induced allergic airway inflammation, MHC class II⁺ ILC3s limit T helper type 2 (Th2) cell responses, eosinophilia, and airway hyperresponsiveness. Furthermore, MHC class II⁺ ILC3s limit a concomitant Th17 cell response and airway neutrophilia. This exacerbated Th17 cell response requires exposure of the lung to microbial stimuli, which can be found associated with house dust mites. These findings demonstrate a critical role for antigen-presenting ILC3s in orchestrating immune tolerance in the airway by restricting pro-inflammatory T cell responses to both allergens and microbes.

Original language	English
Article number	110051
Journal	Cell Reports
Volume	37
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2021.110051
Publication status	Published - 23 Nov 2021

Bibliographical note

Funding Information:
We thank members of the Sonnenberg and Hepworth Laboratories for discussions and critical reading of the manuscript. Research in the Sonnenberg Laboratory is supported by the National Institutes of Health (R01AI143842, R01AI123368, R01AI145989, R01AI162936, R21CA249274, and U01AI095608), the NIAID Mucosal Immunology Studies Team (MIST), the Searle Scholars Program, the American Asthma Foundation Scholar Award, an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, a Wade F.B. Thompson/Cancer Research Institute (CRI) CLIP Investigator grant, the Meyer Cancer Center Collaborative Research Initiative, Linda and Glenn Greenberg, the Dalton Family Foundation, and the Roberts Institute for Research in IBD. G.F.S. is a CRI Lloyd J. Old STAR. Research in the Farber Laboratory is supported by the National Institutes of Health (AI106697). Research in the Hepworth Laboratory is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant number 105644/Z/14/Z), a BBSRC responsive mode grant (BB/T014482/1), and a Lister Institute of Preventative Medicine Prize. Conceptualization, M.R.H. and G.F.S.; methodology, F.T. M.R.H. and G.F.S.; investigation, F.T. R.T.-P. and B.S.; resources, D.L.F. S.W. H.H. and B.N.L.; visualization and writing ? original draft, review & editing, F.T. M.R.H. and G.F.S.; project administration and funding acquisition, M.R.H. and G.F.S. The authors declare no competing interests.

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ILC3s control airway inflammation by limiting T cell responses to allergens and microbesFinal published version, 15.5 MBLicence: CC BY-NC-ND

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title = "ILC3s control airway inflammation by limiting T cell responses to allergens and microbes",

abstract = "Group 3 innate lymphoid cells (ILC3s) critically regulate host-microbe interactions in the gastrointestinal tract, but their role in the airway remains poorly understood. Here, we demonstrate that lymphoid-tissue-inducer (LTi)-like ILC3s are enriched in the lung-draining lymph nodes of healthy mice and humans. These ILC3s abundantly express major histocompatibility complex class II (MHC class II) and functionally restrict the expansion of allergen-specific CD4+ T cells upon experimental airway challenge. In a mouse model of house-dust-mite-induced allergic airway inflammation, MHC class II+ ILC3s limit T helper type 2 (Th2) cell responses, eosinophilia, and airway hyperresponsiveness. Furthermore, MHC class II+ ILC3s limit a concomitant Th17 cell response and airway neutrophilia. This exacerbated Th17 cell response requires exposure of the lung to microbial stimuli, which can be found associated with house dust mites. These findings demonstrate a critical role for antigen-presenting ILC3s in orchestrating immune tolerance in the airway by restricting pro-inflammatory T cell responses to both allergens and microbes.",

author = "Fei Teng and Roser Tach{\'o}-Pi{\~n}ot and Biin Sung and Farber, {Donna L.} and Stefan Worgall and Hamida Hammad and Lambrecht, {Bart N.} and Hepworth, {Matthew R.} and Sonnenberg, {Gregory F.}",

note = "Funding Information: We thank members of the Sonnenberg and Hepworth Laboratories for discussions and critical reading of the manuscript. Research in the Sonnenberg Laboratory is supported by the National Institutes of Health (R01AI143842, R01AI123368, R01AI145989, R01AI162936, R21CA249274, and U01AI095608), the NIAID Mucosal Immunology Studies Team (MIST), the Searle Scholars Program, the American Asthma Foundation Scholar Award, an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, a Wade F.B. Thompson/Cancer Research Institute (CRI) CLIP Investigator grant, the Meyer Cancer Center Collaborative Research Initiative, Linda and Glenn Greenberg, the Dalton Family Foundation, and the Roberts Institute for Research in IBD. G.F.S. is a CRI Lloyd J. Old STAR. Research in the Farber Laboratory is supported by the National Institutes of Health (AI106697). Research in the Hepworth Laboratory is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant number 105644/Z/14/Z), a BBSRC responsive mode grant (BB/T014482/1), and a Lister Institute of Preventative Medicine Prize. Conceptualization, M.R.H. and G.F.S.; methodology, F.T. M.R.H. and G.F.S.; investigation, F.T. R.T.-P. and B.S.; resources, D.L.F. S.W. H.H. and B.N.L.; visualization and writing ? original draft, review & editing, F.T. M.R.H. and G.F.S.; project administration and funding acquisition, M.R.H. and G.F.S. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021",

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AU - Tachó-Piñot, Roser

AU - Sung, Biin

AU - Farber, Donna L.

AU - Worgall, Stefan

AU - Hammad, Hamida

AU - Lambrecht, Bart N.

AU - Hepworth, Matthew R.

AU - Sonnenberg, Gregory F.

N1 - Funding Information: We thank members of the Sonnenberg and Hepworth Laboratories for discussions and critical reading of the manuscript. Research in the Sonnenberg Laboratory is supported by the National Institutes of Health (R01AI143842, R01AI123368, R01AI145989, R01AI162936, R21CA249274, and U01AI095608), the NIAID Mucosal Immunology Studies Team (MIST), the Searle Scholars Program, the American Asthma Foundation Scholar Award, an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, a Wade F.B. Thompson/Cancer Research Institute (CRI) CLIP Investigator grant, the Meyer Cancer Center Collaborative Research Initiative, Linda and Glenn Greenberg, the Dalton Family Foundation, and the Roberts Institute for Research in IBD. G.F.S. is a CRI Lloyd J. Old STAR. Research in the Farber Laboratory is supported by the National Institutes of Health (AI106697). Research in the Hepworth Laboratory is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant number 105644/Z/14/Z), a BBSRC responsive mode grant (BB/T014482/1), and a Lister Institute of Preventative Medicine Prize. Conceptualization, M.R.H. and G.F.S.; methodology, F.T. M.R.H. and G.F.S.; investigation, F.T. R.T.-P. and B.S.; resources, D.L.F. S.W. H.H. and B.N.L.; visualization and writing ? original draft, review & editing, F.T. M.R.H. and G.F.S.; project administration and funding acquisition, M.R.H. and G.F.S. The authors declare no competing interests. Publisher Copyright: © 2021

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N2 - Group 3 innate lymphoid cells (ILC3s) critically regulate host-microbe interactions in the gastrointestinal tract, but their role in the airway remains poorly understood. Here, we demonstrate that lymphoid-tissue-inducer (LTi)-like ILC3s are enriched in the lung-draining lymph nodes of healthy mice and humans. These ILC3s abundantly express major histocompatibility complex class II (MHC class II) and functionally restrict the expansion of allergen-specific CD4+ T cells upon experimental airway challenge. In a mouse model of house-dust-mite-induced allergic airway inflammation, MHC class II+ ILC3s limit T helper type 2 (Th2) cell responses, eosinophilia, and airway hyperresponsiveness. Furthermore, MHC class II+ ILC3s limit a concomitant Th17 cell response and airway neutrophilia. This exacerbated Th17 cell response requires exposure of the lung to microbial stimuli, which can be found associated with house dust mites. These findings demonstrate a critical role for antigen-presenting ILC3s in orchestrating immune tolerance in the airway by restricting pro-inflammatory T cell responses to both allergens and microbes.

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ILC3s control airway inflammation by limiting T cell responses to allergens and microbes

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