A regulatory T cell Notch4–GDF15 axis licenses tissue inflammation in asthma

Abstract

Elucidating the mechanisms that sustain asthmatic inflammation is critical for precision therapies. We found that interleukin-6- and STAT3 transcription factor-dependent upregulation of Notch4 receptor on lung tissue regulatory T (Treg) cells is necessary for allergens and particulate matter pollutants to promote airway inflammation. Notch4 subverted Treg cells into the type 2 and type 17 helper (TH2 and TH17) effector T cells by Wnt and Hippo pathway-dependent mechanisms. Wnt activation induced growth and differentiation factor 15 expression in Treg cells, which activated group 2 innate lymphoid cells to provide a feed-forward mechanism for aggravated inflammation. Notch4, Wnt and Hippo were upregulated in circulating Treg cells of individuals with asthma as a function of disease severity, in association with reduced Treg cell-mediated suppression. Our studies thus identify Notch4-mediated immune tolerance subversion as a fundamental mechanism that licenses tissue inflammation in asthma.

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Fig. 1: Notch4 expression on lung Treg cells in allergic airway inflammation.
Fig. 2: Notch4 expression on lung Treg cells licenses allergic airway inflammation.
Fig. 3: Notch4-dependent transcriptional programs in lung Treg cells.
Fig. 4: Regulation of allergic airway inflammation by Notch4-dependent Hippo and Wnt pathway.
Fig. 5: Notch4 destabilizes Treg cells in a Hippo pathway-dependent manner.
Fig. 6: Notch4 promotes ILC2 activation via a GDF15-dependent mechanism.
Fig. 7: GDF15 regulates ILC2 response in airway inflammation.
Fig. 8: Notch4 expression on circulating Treg cells segregates with asthma severity.

Data availability

The data presented in the manuscript, including de-identified patient results, will be made available to investigators after a request to the corresponding author. Any data and materials to be shared will be released via a material transfer agreement. RNA-seq datasets have been deposited in the Gene Expression Omnibus with the accession no. GSE151763. Source data are provided with this paper.

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Acknowledgements

This work was supported by National Institutes of Health grants (nos. R01 AI115699 and R01 AI065617 to T.A.C., U01AI110397 and R01 HL137192 to W.P.) a National Health and Medical Research Council grant (no. APP1163249 to B.G.) and a German Research Society grant (no. HA 8465/1-1 to H.H.).

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Authors

Contributions

H.H. and T.A.C. designed experiments. H.H., E.S-V, M.B., A.M., Y.C, L-M.C. and S.A. performed experiments and developed experimental models. E.C., S.B., A.C. and W.P. recruited patients and analyzed their demographics. K.S.A. and B.G. analyzed the RNA-seq data. J.M.L.C. and R.S.G. provided RoraCre and RoraCreIl4∆/∆Il13∆/∆ mice. C.S. and A.J.M provided UFPs. H.H. and T.A.C. wrote the manuscript.

Corresponding author

Correspondence to Talal A. Chatila.

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Competing interests

T.A.C., H.H. and A.M. are inventors on published US patent application no. WO2019178488A1 submitted by the Children’s Medical Center Corporation, titled ‘Method for treating asthma or allergic disease’. B.G. is a director of Pacific Analytics and SMRTR, Australia; a founding member of the International Cerebral Palsy Genetics Consortium; and a member of the Australian Genomics Health Alliance. W.P. is a Consultant for Genentech, Novartis, Regeneron, Sanofi Genzyme and Glaxo Smith Kline, and receives clinical trial support from Genentech, Novartis, Regeneron, Circassia, Thermo Fisher, Monaghan, Lincoln Diagnostics, Alk Abello and Glaxo Smith Kline.

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Peer review information Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Notch4 expression on lung Treg cells in allergic airway inflammation.

a-c, Flow cytometric analysis, cell frequencies and (MFI) of Notch1, 2 and 3 expression on lung Treg and Teff cells in Foxp3YFPCre (n = 5). d, Cell frequencies of Notch4 expression on OT-II+CD4+Foxp3+ T cells generated in co-cultures with sham or OVA323-339 + UFP-pulsed alveolar macrophages without or with IL-1β, IL-25, IL-33, TSLP or TNF (n = 5). e, ChIP assays for the binding of STAT3 and control (IgG) antibodies to the Notch1, 2 and 3 promoters in lung Treg cells of OVA + UFP-treated Foxp3YFPCre, and Foxp3YFPCreStat3∆/∆ mice (n = 5). Each symbol represents one mouse. Numbers in flow plots indicate percentages. Error bars indicate SEM. Statistical tests: Oneway ANOVA with Dunnett’s post hoc analysis (a-c); two-way ANOVA with Sidak’s post hoc analysis (d,e). **P < 0.01, ***P < 0.001, ****P < 0.0001. Data representative of two or three independent experiments. Source data

Extended Data Fig. 2 Notch4 expression on lung Treg cells licenses allergic airway inflammation.

a, RT-PCR analysis of Notch4 expression in CD4Cre mice in B-cells and T-cells (n = 5). b, RT-PCR analysis of Notch4 expression in Foxp3YFPCre mice in both Treg and Teff cells (n = 5). c,d, IL-4 and IFN-γ expression in lung Foxp3+CD4+ Treg. (c) and Foxp3CD4+Teff cells. (d) derived from the respectively treated Foxp3YFPCre, CD4CreNotch4∆/∆ and Foxp3YFPCreNotch4∆/∆ mice (n = 5). e, Airway hyperresponsiveness in Foxp3YFPCre sensitized either with PBS or OVA, then challenged with OVA + UFP following transfer of OTII+Foxp3YFPCre or OTII+Foxp3YFPCreNotch4∆/∆ iTreg cells (n = 5). f, Eosinophil numbers for the respective mouse groups (n = 5). g, IL-4, IL-13, IL-17 and IFNγ expression in lung Foxp3CD4 Teff cells. Each symbol represents one mouse (n = 5). Error bars indicate SEM. Statistical tests: two-way ANOVA with Sidak’s post hoc analysis (a,c,d); One-way ANOVA with Dunnett’s post hoc analysis (e,f). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Data representative of two or three independent experiments. Source data

Extended Data Fig. 3 Allergic airway inflammatory responses in mice with Treg cell-specific Pofut1 or Rbpj1 deletion.

a, Representative PAS-stained sections of lung tissues isolated from Foxp3YFPCre, Foxp3YFPCrePofut1∆/∆ or Foxp3YFPCreRbpj1∆/∆ mice segregated into PBS, OVA or OVA + UFP-treated groups (200X magnification). b, Inflammation scores in the respective lung tissues. c, AHR in the respective mouse groups in response to methacholine. d,e, serum total and OVA-specific IgE concentrations. f,g, absolute numbers of lung CD4+ T cells and eosinophils. h,i, IL-4, IL-13, IL-17 and IFNγ expression in lung Foxp3+CD4+ Treg (h) and Foxp3CD4+Teff cells (i). Each symbol represents an independent sample. Error bars indicate SEM. Statistical tests: two-way ANOVA with Sidak’s post hoc analysis (b-i). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Data representative of two or three independent experiments. n = 5 mice per group. Source data

Extended Data Fig. 4 Allergic airway inflammatory responses in mice with Treg cell-specific Notch1 or Notch2 deletion or global Notch3 deletion.

a-c, AHR in Foxp3YFPCre, Foxp3YFPCreNotch1∆/∆, Foxp3YFPCreNotch2∆/∆, or Foxp3YFPCreNotch3–/– mice segregated into PBS, OVA or OVA + UFP-treated groups (200X magnification). d, serum OVA-specific IgE concentrations. e,f, absolute numbers of lung CD4+ T cells and eosinophils. g,h, IL-4, IL-13, and IL-17 expression in lung Foxp3CD4+Teff (g) and Foxp3+CD4+Treg cells (h). Each symbol represents an independent sample. Error bars indicate SEM. Statistical tests: two-way ANOVA with Sidak’s post hoc analysis a-h. Data representative of two or three independent experiments. n = 5 mice per group. Source data

Extended Data Fig. 5 Treg cell-specific Il6r and stat3 deletions attenuate allergic airway inflammation.

a, Representative PAS-stained sections of lung tissues isolated from Foxp3YFPCre, Foxp3YFPCreIl6r∆/∆ or Foxp3YFPCreStat3∆/∆ mice segregated into PBS, OVA or OVA + UFP-treated groups (200X magnification). b, Inflammation scores in the respective lung tissues. c, AHR in the respective mouse groups in response to methacholine. d,e, serum total and OVA-specific IgE concentrations. f,g, absolute numbers of lung CD4+ T cells and eosinophils. h,i, IL-13 and IL-17 expression in lung Foxp3+CD4+ Treg (h) and Foxp3CD4+ Teff cells (i). Each symbol represents an independent sample. Error bars indicate SEM. Statistical tests: two-way ANOVA with Sidak’s post hoc analysis (b-i). *P < 0.05, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Data representative of two or three independent experiments. n = 5 mice per group. Source data

Extended Data Fig. 6 Treg cell-specific Notch4 deletion rescues HDM induced allergic airway inflammation.

a, scheme of the house dust mite (HDM) airway inflammation protocol. b, Representative PAS-stained sections of lung tissues isolated from Foxp3YFPCre or Foxp3YFPCreNotch4∆/∆ mice segregated into PBS, OVA or OVA + UFP-treated groups (200X magnification). c, Inflammation scores in the respective lung tissues. d, AHR in the respective mouse groups in response to methacholine. e, serum total IgE concentrations. (f-h), absolute numbers of lung CD4+ T cells, neutrophils and eosinophils. i,k, IL-4, IL-13, IL-17 and IFNγ expression in lung Foxp3+CD4+ Treg (i) and Foxp3CD4+ Teff cells (k). Each symbol represents an independent sample. Numbers in flow plots indicate percentages. Error bars indicate SEM. Statistical tests: two-way ANOVA with Sidak’s post hoc analysis (c-k). **P < 0.01, ***P < 0.001, ****P < 0.0001. Data representative of two or three independent experiments. n = 5 mice per group. Source data

Extended Data Fig. 7 Treg cell-specific Notch4 deletion rescues chronic allergic airway inflammation.

a, Scheme for the chronic airway inflammation mouse protocol b, Representative Sirius-Red-stained sections of lung tissues isolated from Foxp3YFPCre or Foxp3YFPCreNotch4∆/∆ mice segregated into PBS, OVA or OVA + UFP-treated groups (200X magnification). c, Collagen disposition measurement in the respective lung tissues. d, AHR in the respective mouse groups in response to methacholine. e,f, absolute numbers of lung CD4+ T cells and eosinophils. g,h, IL-4, IL-13, and IL-17 expression in lung Foxp3+CD4+ Treg (g) and Foxp3CD4+Teff cells (h). i, Serum OVA-specific IgE titers in the respective groups. Each symbol represents an independent sample. Error bars indicate SEM. Statistical tests: two-way ANOVA with Sidak’s post hoc analysis (c-h). *P < 0.05, ****P < 0.0001. Data representative of two or three independent experiments. n = 5 mice per group. Source data

Extended Data Fig. 8 Notch receptor expression in human Treg and Teff cells.

a,b, Flow cytometric analysis, cell frequencies and mean fluorescence intensity (MFI) of Notch1, 2 and 3 expression in peripheral blood Treg cells (a) and Teff cells (b) of control and asthmatic subjects, the latter segregated for asthma severity (control n = 22, M.P n = 15, Mod n = 16. S.P n = 11). c, Flow cytometric analysis and cell frequencies of Notch4 peripheral blood Treg cells of healthy control, food allergy (FA), eczema and FA + eczema (Control n = 37, FA n = 28, Eczema n = 10 and FA + Eczema n = 20) d, Serum GDF15 concentrations in asthmatic subjects plotted as a function of Notch4 expression on circulating Treg cells (n = 73) e, Cell frequencies of Notch4 expression in peripheral blood Treg cells in healthy subjects, allergic and non-allergic asthmatics (control = 56, non-allergic n = 21, allergic n = 85). Error bars indicate SEM. Statistical tests: One-way ANOVA with Dunnett’s post hoc analysis. (a-c,e); simple regression analysis (d). ***P < 0.001, ****P < 0.0001. Data representative of two or three independent experiments. Source data

Supplementary information

Supplementary information

Supplementary Table 1.

Reporting Summary

Supplementary Dataset 1

RNA-seq analysis of lung Treg cells from OVA + UFP-treated Foxp3YFPCre and FoxpeYFPCreNotch4∆/∆.

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Harb, H., Stephen-Victor, E., Crestani, E. et al. A regulatory T cell Notch4–GDF15 axis licenses tissue inflammation in asthma. Nat Immunol (2020). https://doi.org/10.1038/s41590-020-0777-3

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