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Regulatory T cell-derived IL-1Ra suppresses the innate response to respiratory viral infection

Nature Immunology volume 24, pages 2091–2107 (2023)Cite this article

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Abstract

Regulatory T (Treg) cell modulation of adaptive immunity and tissue homeostasis is well described; however, less is known about Treg cell-mediated regulation of the innate immune response. Here we show that deletion of ST2, the receptor for interleukin (IL)-33, on Treg cells increased granulocyte influx into the lung and increased cytokine production by innate lymphoid and γδ T cells without alteration of adaptive immunity to influenza. IL-33 induced high levels of the interleukin-1 receptor antagonist (IL-1Ra) in ST2+ Treg cells and deletion of IL-1Ra in Treg cells increased granulocyte influx into the lung. Treg cell-specific deletion of ST2 or IL-1Ra improved survival to influenza, which was dependent on IL-1. Adventitial fibroblasts in the lung expressed high levels of the IL-1 receptor and their chemokine production was suppressed by Treg cell-produced IL-1Ra. Thus, we define a new pathway where IL-33-induced IL-1Ra production by tissue Treg cells suppresses IL-1-mediated innate immune responses to respiratory viral infection.

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Fig. 1: Early deletion of Treg cells during influenza increases lung granulocytes and improves survival.
Fig. 2: ST2 is expressed in a population of Treg cells in the lung early during influenza infection.
Fig. 3: Deletion of ST2 on Treg cells increases innate immune responses in the lung to influenza.
Fig. 4: Deletion of ST2 on Treg cells improves viral control and survival to influenza.
Fig. 5: Neutrophils mediate improved survival in influenza-infected Il1rl1fl/flFoxp3YFPCre mice.
Fig. 6: Treg cells produce IL-1Ra in response to IL-33-induced ST2 signaling.
Fig. 7: Deletion of IL-1Ra in Treg cells increases innate immunity to influenza.
Fig. 8: Adventitial fibroblasts express high levels of IL-1R1 and are suppressed by Treg cell-produced IL-1Ra.

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Data availability

RNA-seq data generated in this paper have been deposited in the NCBI GEO under accession GSE173249. The RNA-seq datasets used but generated by others include GEO accessions GSE125492 and GSE132771. Source data are provided with this paper.

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Acknowledgements

This work was supported by NIH grants R01AI040618, R01AI168131 and T32HL116275 (to A.D.L.), NIH K08AI125816, a Parker B. Francis Fellowship Grant and an American Lung Association Biomedical Research Grant (to J.W.G). Cytometric findings reported here were performed in the Massachusetts General Hospital Department of Pathology Flow and Image Cytometry Research Core, which obtained support from the NIH Shared Instrumentation program with grants 1S10OD012027, 1S10OD016372, 1S10RR020936 and 1S10RR023440.

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Authors and Affiliations

  1. Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Jason W. Griffith, Lucas D. Faustino, Victoria I. Cottrell, Keshav Nepal, Rebecca Suet-Yan Chiu, Michael C. Jones & Andrew D. Luster

  2. Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Jason W. Griffith & Lida P. Hariri

  3. Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Lucas D. Faustino, Victoria I. Cottrell, Keshav Nepal, Rebecca Suet-Yan Chiu, Michael C. Jones & Andrew D. Luster

  4. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

    Lida P. Hariri

  5. Harvard Chan Bioinformatics Core, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Amélie Julé

  6. Division of Rheumatology, University Hospitals of Geneva and University of Geneva Faculty of Medicine, Geneva, Switzerland

    Cem Gabay

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Contributions

J.W.G. designed, performed, analyzed and interpreted experiments and wrote the paper; L.D.F. provided mice and participated in data analysis and interpretation; R.S.-Y.C., M.C.J., V.I.C., A.J., L.P.H. and K.N. collected, assembled and interpreted data; C.G. provided mice; and A.D.L. conceptualized and designed study, analyzed and interpreted data, and contributed to writing the paper.

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Correspondence to Andrew D. Luster.

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Nature Immunology thanks Evangelos Andreakos and Ari Molofsky for their contribution to the peer review of this work. Peer reviewer reports are available. Primary Handling Editor: L. A. Dempsey, in collaboration with the Nature Immunology team.

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Extended data

Extended Data Fig. 1 Deletion of Treg cells in Foxp3DTR mice.

(a-j) Wild-type (WT) C57BL/6J controls (white circles), Foxp3ERT2Cre controls (grey circles) and Foxp3DTR mice (green circles) were infected with 0.3LD50 PR8 influenza and all strains were treated with DT on day 2 post infection to deplete Treg cells in the Foxp3DTR mice, and harvested on day 5 (WT n = 9, Foxp3ERT2Cre n = 10, Foxp3DTR n = 16), 7 (WT n = 11, Foxp3ERT2Cre n = 11, Foxp3DTR n = 9), and 10 (WT n = 10, Foxp3ERT2Cre n = 9, Foxp3DTR n = 5) post-infection. Uninfected mice treated with DT and harvested 3 days later were indicated on the X axis as ∅ (WT n = 7, Foxp3ERT2Cre n = 4, Foxp3DTR n = 4). (a) Representative gating strategy to determine the number of i.v. antibody-negative (Ab–) alveolar macrophages (SiglecF+CD11chi), eosinophils (SiglecF+CD11clo-int), DCs (SiglecF–CD11chi, MHCIIhi), inflammatory monocytes (SiglecF−CD11clo-intCD11b+CD64+F4/80int-hiLy6C+) and neutrophils (CD11c–MHCII–F480–CD64–CD11b+Ly6G+) in the lung during influenza infection. BAL was assessed in a similar manner except that all cells in the BAL were negative for the i.v. Ab. The ratio of Ly6G+CD11b+ neutrophils compared to total viable i.v. Ab– parenchymal cells was also assessed. (b) Total number of viable cells that were defined as lung parenchymal cells by i.v. Ab– staining. (c) Total number of viable BAL cells. (d) Total number of Ly6C+ monocytes in the BAL. Total number of IFNγ+ (e) and IL-17+ (f) CD4+ T cells as well as IFNγ+ CD8+ T cells (g) and IL-17-producing γδ T cells (h) as determined by intracellular cytokine staining. IFNγ Foxp3ERT2Cre n = 10, Foxp3DTR n = 10) (i) and CXCL5 (Foxp3ERT2Cre n = 6, Foxp3DTR n = 6) (j) levels in the BAL on day 5 as measured by ELISA and normalized to total protein (DT in these experiments was given on days 2 and 4 post infection). (k) Survival in the WT controls (black) and Foxp3DTR (green) mice after infection of an LD50 dose of PR8 influenza and administration of one dose of DT on day 9 of infection. Uninfected Foxp3DTR mice treated with DT were also included (grey line). Unless otherwise indicated, data are pooled from 2-3 experiments and each dot represents one mouse. Statistics for (b-h) by two-way ANOVA with Sidak′s multiple comparisons test and for (i,j) two-tailed unpaired Student’s T-test. Statistical significance for the survival experiment (k) was assessed by Log-Rank (Mantel-Cox) test. Data presented in box and whiskers plots: whiskers are max and min, box 25–75 percentile and line is median. P values indicated in the figure.

Source data

Extended Data Fig. 2 ST2+ Treg cells expand in the lung and BAL early during influenza.

(a-i) Foxp3YFPCre mice were infected with influenza and harvested on the indicated day of infection. (a) Representative gating strategy used to analyze lung parenchymal (i.v. Ab–) Treg cells and the expression of ST2 and CXCR3. (b-d) Representative flow cytometry, number and percentage of Treg cells to CD4+ T cells in the lung i.v. Ab+ blood compartment (b), the lung i.v. Ab– parenchyma (c) and the BAL (d) (Representative experiment of 2 performed, day 0: n = 3, day 4: n = 4, lung day 7: n = 5, BAL day 7 n = 6, lung day 11: n = 4, BAL day 11: n = 6, day 14: n = 3). (e) Representative flow cytometry (left) and total number (right) of ST2+ (blue) and CXCR3+ (red) and ST2–CXCR3– CD3+CD4+Foxp3+ Treg cells isolated from the BAL on the indicated day post influenza infection (Representative experiment of 2 performed, day 0: n = 5, day 4: n = 3, day 7: n = 6, day 11: n = 5). (f) Representative flow cytometry comparing ST2 and CXCR3 expression on parenchymal and blood Treg cells isolated from lungs harvested on indicated day post influenza infection. (g) Representative flow cytometry (top) and % positive cells (bottom) for CD69 expression on parenchymal and blood Treg cells isolated from the lung of influenza infected mice on day 5 of infection (Representative experiment of 2 performed, n = 4). (h) Representative flow cytometry of ST2 and Helios expression on parenchymal CD3+CD4+Foxp3+ Treg cells isolated from the lung from mice on the indicated day of infection. (i) Representative flow cytometry of ST2 and KLRG1 expression (top) or CXCR3 and KLRG1 expression (bottom) on parenchymal CD3+CD4+Foxp3+ Treg cells isolated from the lung from mice on the indicated day of infection. All statistics were calculated by ordinary one-way ANOVA with Tukey’s multiple comparisons except for (g) which used an unpaired two-tailed Student’s t-test. For line graphs: Error bars, mean ± SD. For box and whiskers plots: whiskers are max and min, box 25–75 percentile and line is median. P values are indicated in plots.

Source data

Extended Data Fig. 3 Conditional deletion of ST2 on Treg cells altered Treg cell activation and the innate immune response to infection.

(a-h) Foxp3YFPCre controls (white) and Il1rl1fl/fl littermate controls (grey) and Il1rl1fl/flFoxp3YFPCre mice (blue) were infected with 0.3LD50 PR8 influenza and harvested on the indicated day post infection. (a) Treg cells (left) and Foxp3–CD4+ T cells (right) were sorted from the lungs on day 7 of infection and subjected to RT–qPCR for analysis of Il1rl1 mRNA levels (Each dot represents the mean of 1 experiment, Foxp3YFPCre n = 4, Il1rl1fl/flFoxp3YFPCre n = 3). (b) MFI of CD69 expression (left; Foxp3YFPCre n = 5, Il1rl1fl/flFoxp3YFPCre n = 5) and % cells positive for Ki67(right; Foxp3YFPCre n = 6, Il1rl1fl/flFoxp3YFPCre n = 5) on CD3+CD4+Foxp3+ Treg cells in the lung parenchyma on day 4 of infection. (c) MFI of KLRG1 (left) and Foxp3 (right) expression of CD3+CD4+Foxp3+ Treg cells on day 7 of infection in the indicated mouse strains (Il1rl1fl/fl n = 4, Foxp3YFPCre n = 6, Il1rl1fl/flFoxp3YFPCre n = 4). (d) Representative flow cytometry and total number of CD3+CD4+Foxp3+ Treg cells in the lung that stained positive for the indicated cytokines on day 9 of influenza infection in Foxp3YFPCre (white, n = 8) and Il1rl1fl/fl (grey, n = 3) littermate controls and Il1rl1fl/flFoxp3YFPCre (blue, n = 6) mice. (e) Flow cytometry was used to quantify the number of SiglecF–CD11cloCD11b+CD64–F4/80−Ly6G+ neutrophils in the BAL (far left), SiglecF+CD11clo eosinophils in the BAL (left), SiglecF–CD11c–CD11b+CD64+F4/80int-hiLy6C+ inflammatory monocytes in the BAL (right) and, SiglecF+CD11chi alveolar macrophages in the BAL (far right) in the lung on the indicated day post infection in Foxp3YFPCre (white, day 0 n = 3, day 4 n = 6, day 7 n = 13, day 9 n = 14, day 11 n = 14) and Il1rl1fl/fl(grey, day 7 n = 8, day 9 n = 3, day 11 n = 2) controls and Il1rl1fl/flFoxp3YFPCre (blue, day 0 n = 4, day 4 n = 9, day 7 n = 12, day 9 n = 11, day 11 n = 12) mice. (f) Cytokine and chemokine levels in the BAL of Foxp3YFPCre control (white, n = 16) and Il1rl1fl/flFoxp3YFPCre (blue, n = 11) mice on day 7 of influenza infection as assessed by Luminex. (g) Representative flow cytometry of ST2 expression of CD45+Lineage−Thy1.2+ innate lymphoid cells (left, numbers indicate percentage of ST2+ cells with STD) and quantification of the total number of CD45+Lineage−Thy1.2+ST2+ ILC2s (right). Foxp3YFPCre (white; n = 5) and Il1rl1fl/fl(grey; n = 6) controls and Il1rl1fl/flFoxp3YFPCre (blue; n = 4) mice. (h) Total number of CD3−NK1.1+ NK cells in the lung on the indicated day of infection. Unless otherwise indicated, data are pooled from 2-3 experiments and each dot represents one mouse. All statistics were calculated by ordinary one-way ANOVA with Tukey’s multiple comparisons except for (a,b) which used an unpaired two-tailed Student’s t-test and (h) which was calculated by unpaired t-test with Holm-Sidak adjustment for multiple comparisons. For box and whiskers plots: whiskers are max and min, box 25–75 percentile and line is median. Fold difference between groups is indicated by ×. P values as indicated in plots.

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Extended Data Fig. 4 Deletion of ST2 in Treg cells increased the innate immune response to influenza and improved viral control.

(a-f) Foxp3ERT2Cre control (light grey) treated with tamoxifen and Il1rl1fl/flFoxp3ERT2Cre (black/blue) treated with oil as another control were compared with Il1rl1fl/flFoxp3ERT2Cre mice (light blue) treated with tamoxifen to specifically delete the Il1rl1 gene in Treg cells. After a 14-day tamoxifen washout, mice were infected with influenza and analyzed on day 7. (a) Representative flow cytometry of ST2 and CXCR3 expression on lung (i.v. Ab−) Treg cells. (b) MFI of ST2 expression on lung Treg cells (i.v. Ab−, CD3+CD4+Foxp3+) (Foxp3ERT2Cre +TAM n = 13, Il1rl1fl/flFoxp3ERT2Cre +oil n = 12, Il1rl1fl/flFoxp3ERT2Cre +TAM n = 13). (c) MFI of ST2 expression on lung eosinophils (i.v.Ab−, SiglecF+, CD11clo) (Foxp3ERT2Cre +TAM n = 4, Il1rl1fl/flFoxp3ERT2Cre +oil n = 4, Il1rl1fl/flFoxp3ERT2Cre +TAM n = 5). (d) MFI of ST2 expression on innate lymphoid cells (CD45+, Lineage−, Thy1.2+)(Foxp3ERT2Cre +TAM n = 8, Il1rl1fl/flFoxp3ERT2Cre +oil n = 9, Il1rl1fl/flFoxp3ERT2Cre +TAM n = 9). (e) The number of neutrophils and eosinophils in the BAL (Foxp3ERT2Cre +TAM n = 13, Il1rl1fl/flFoxp3ERT2Cre +oil n = 12, Il1rl1fl/flFoxp3ERT2Cre +TAM n = 13). (f) The number of lung IL-17+ γδ T cells and lung IL-5+ ILC2s as assessed by flow cytometry (Foxp3ERT2Cre +TAM n = 9, Il1rl1fl/flFoxp3ERT2Cre +oil n = 8, Il1rl1fl/flFoxp3ERT2Cre +TAM n = 8). (g) Influenza Polymerase levels as determined by RT–qPCR in the lungs of Foxp3YFPCre controls (white; day 0 n = 9, day 4 n = 23, day 7 n = 24, day 11 n = 31), Il1rl1fl/fl (grey; day 7 n = 7, day 11 n = 4) littermate controls and Il1rl1fl/flFoxp3YFPCre mice (blue; day 0 n = 4, day 4 n = 16, day 7 n = 21, day 11 n = 19) infected with 0.3LD50 PR8 influenza. (h) Matrix Protein 1 RNA levels as determined by RT–qPCR in the lungs of Foxp3YFPCre controls (white; day 0 n = 3, day 4 n = 16, day 7 n = 16, day 11 n = 23) and Il1rl1fl/flFoxp3YFPCre mice (blue; day 0 n = 4, day 4 n = 12, day 7 n = 12, day 11 n = 11) infected with 0.3LD50 PR8 influenza. (i) Weight loss in Foxp3YFPCre (white) controls and Il1rl1fl/flFoxp3YFPCre mice (blue) after influenza infection (Error bars, mean± SEM). Unless otherwise indicated, data are pooled from 2–4 experiments and each dot represents one mouse. Statistics for (b-f) were calculated by ordinary one-way ANOVA with Tukey’s multiple comparisons. Statistics for (g and h) were calculated by unpaired Student’s t-tests with Holm-Sidak adjustment for multiple comparisons. Statistics for (i) were calculated by two-way ANOVA with Sidak′s multiple comparisons test. For box and whiskers plots: whiskers are max and min, box 25–75 percentile and line is median. Fold difference between groups is indicated by ×. P values are indicated in plots.

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Extended Data Fig. 5 Deletion of Myd88 in Treg cells phenocopied the immune response to influenza in the Il1rl1fl/flFoxp3YFPCre mice.

(a-i) Foxp3YFPCre controls (white) and myd88fl/flFoxp3YFPCre mice (purple) were infected with 0.3LD50 dose PR8 influenza and harvested on the indicated day post infection. (a) Treg cells and Foxp3– CD4+ T cells were sorted from the lungs on day 7 of infection and Myd88 expression was analyzed by RT–qPCR (Each dot represents the pooled mean of 1 experiment: Foxp3YFPCre n = 4, myd88fl/flFoxp3YFPCre n = 3). (b) The indicated cell types were sorted from the lungs on day 7 of infection and Myd88 expression was analyzed by RT–qPCR (Each dot represents the pooled mean of 1 experiment: Foxp3YFPCre n = 3, myd88fl/flFoxp3YFPCre n = 2). (c) Representative flow cytometry of ST2 and CXCR3 expression on lung parenchymal (i.v. Ab–) CD3+CD4+Foxp3+ Treg cells on day 7 of influenza infection. (d) Total number of lung parenchymal (i.v. Ab–) CD3+CD4+Foxp3+ Treg cells in the indicated strains on the indicated day of influenza infection (left) and the percentage of Treg cells expressing ST2 in the same mice (right) (Foxp3YFPCre, day 0 n = 3, day 4 n = 11, day 7 n = 10, day 9 n = 6; myd88fl/flFoxp3YFPCre, day 0 n = 6, day 4 n = 11, day 7 n = 8, day 9 n = 5). (e-f) Representative flow cytometry (left) and number (right) of CD11c–SiglecF–CD11b+CD64–LygG+ neutrophils (e) and SiglecF+CD11clo eosinophils (f) in the BAL on the indicated day of infection (Foxp3YFPCre, day 0 n = 5, day 4 n = 8, day 7 n = 5, day 9 n = 4, day 11 n = 6; myd88fl/flFoxp3YFPCre, day 0 n = 6, day 4 n = 11, day 7 n = 9, day 9 n = 4, day 11 n = 6). (g-i) Representative flow cytometry at day 7 (left) and total number on the indicated day of infection (right) of IL-17+ γδ T cells in the lungs (g) on the indicated day of infection. (h-i) Number of IFNγ+CD4+ T cells (h) and IFNγ+CD8+ T cells (i) in the lungs of the indicated Foxp3YFPCre control and Myd88fl/flFoxp3YFPCre mice on the indicated day of influenza infection(Foxp3YFPCre, day 0 n = 4, day 4 n = 11, day 7 n = 5, day 9 n = 10; myd88fl/flFoxp3YFPCre, day 0 n = 6, day 4 n = 11, day 7 n = 5, day 9 n = 10). Unless otherwise indicated, data are pooled from 2-3 experiments and each dot represents one mouse, except for (a,b) where each dot represents the mean value from an individual experiment. Statistics for (a) were calculated by an unpaired two-tailed t-test. Statistics for (b-i) were calculated by unpaired t-test with Holm-Sidak adjustment for multiple comparisons. For box and whiskers plots: whiskers are max and min, box 25–75 percentile and line is median. P values are indicated in plots.

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Extended Data Fig. 6 Distinct gene expression patterns in ST2+ and CXCR3+ Treg cells in the lung of influenza infected mice.

(a-g) Bulk RNAseq was performed on spleen Treg cells from uninfected mice (black) and on sorted ST2+ (blue) and CXCR3+ (red) Treg cells isolated from the pooled lungs of Foxp3YFPCre mice on day 7 of influenza infection and performed in 3 independent experiments (n = 3). (a) Principal component analysis of the different Treg cell populations. (b) Venn diagram of differentially expressed genes in the ST2+ and CXCR3+ Treg subsets compared to each other and to naïve total spleen Treg cells. (c) Heat map of selected transcription factor expression in the indicated Treg cell populations performed in triplicate. (d) Transcription factor RNA levels in the indicated cell populations: As above, spleen Treg cells from uninfected mice (spleen), sorted ST2+ Treg cells (ST2+) and CXCR3+ Treg cells (CXCR3+) isolated from the lungs of pooled Foxp3YFPCre mice on day 7 of influenza infection. (e) Heat map of selected trafficking gene expression in the indicated Treg cell populations. (f) Selected trafficking gene RNA expression levels in the indicated Treg cell populations. (g) Selected Treg cell effector gene RNA expression levels in the indicated Treg cell populations. Floating bars: min to max, line median. All statistics were calculated by unpaired two tailed Student’s t-test. P values indicated in figure.

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Extended Data Fig. 7 IL-1Ra is a critical mediator of inflammatory responses to influenza.

(a-k) Il1rn+/+ littermate controls (white circles, n = 8) and Il1rn–/– mice (yellow circles, n = 7) were infected with influenza and harvested on day 7. (a-b) The percentage (left) and number (right) of CD11b+Ly6G+ neutrophils in the lung parenchyma (a) and BAL (b). (c) RNA levels of Cxcl5 relative to B2m in the lungs on day 7 of infection as determined by RT–qPCR. (d-e) The percentage (left) and number (right) of SiglecF+CD11clo eosinophils in the lung parenchyma (d) and BAL (e). (f) Percentage (left) and number (right) of IL-17-producing γδ T cells in the lung as assessed by ICS staining on day 7 of infection. (g-h) Percentage and number of CD4+ T cells (g) and CD8+ T cells (h) in the lung that were positive for IFNγ and IL-17 expression as assessed by ICS. (i-k) Percentage and number of CD4+Foxp3+ Treg cells in the lung parenchyma was determined (i) as well as the percentage and number of Treg cells that expressed ST2 (j). (k) Influenza Nucleoprotein (left) and Polymerase (right) RNA levels in the lungs on day 7 of influenza infection. (l) Survival of the indicated strains after 0.3LD50 dose influenza. Unless otherwise indicated, data are pooled from 2-3 experiments and each dot represents one mouse. All statistics were calculated by unpaired two-tailed t-test except the survival experiment (l) which was assessed by Log-Rank (Mantel-Cox) test. Box and whiskers plots: whiskers are max and min, box 25–75 percentile and line is median. P values are indicated in plots.

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Extended Data Fig. 8 Deletion of Il1rn in Treg cells affected the innate but not adaptive response to influenza.

(a-g) Foxp3YFPCre controls (white) and Il1rnfl/fl (grey) littermate controls and Il1rnfl/flFoxp3YFPCre (orange) mice were infected with 0.3LD50 PR8 influenza and harvested on the indicated day post infection. (a-b) Representative flow cytometry of the percentage of CD11b+Ly6G+ neutrophils (a) and SiglecF+CD11clo eosinophils (b) compared to total viable cells (left) and total number of neutrophils (right) in the BAL in Foxp3YFPCre controls (white, day 0 n = 6, day 5 n = 7, day 7 n = 20, day 9 n = 16) and Il1rnfl/fl (grey, day 0 n = 8, day 5 n = 10, day 7 n = 14, day 9 n = 6) littermate controls and Il1rnfl/flFoxp3YFPCre (orange, day 0 n = 7, day 5 n = 9, day 7 n = 12, day 9 n = 11) mice on day 7 of infection. (c) Representative flow cytometry of the percentage of IL-17+ γδ T cells (right) and total number of IL-17+ γδ T cells (left) in the lung of Foxp3YFPCre controls (n = 7) and Il1rnfl/fl (grey, n = 10) littermate controls and Il1rnfl/flFoxp3YFPCre (orange, n = 9) mice on day 5 of influenza as determined by ICS. (d) Number of IFNγ+CD4+ T cells (left) and IFNγ+CD8+ T cells (right) in the lung as assessed by ICS in Foxp3YFPCre controls (white, n = 8) and Il1rnfl/flFoxp3YFPCre (orange, n = 8) mice on day 7 of infection. (e-f) Percentage (left) and number (right) of total CD4+Foxp3+ Treg cells (e) and ST2+ Treg cells (f) in the lung parenchyma assessed by flow cytometry in Foxp3YFPCre controls (white, n = 14) and Il1rnfl/flFoxp3YFPCre (orange, n = 11) mice on day 7 of infection. (g) Influenza NP RNA levels in the lungs determined by RT–qPCR on day 7 of influenza infection in Foxp3YFPCre controls (white, n = 10) and Il1rnfl/flFoxp3YFPCre (orange, n = 12) mice were infected with 0.3LD50 PR8 influenza. (h) The number of neutrophils (left) and eosinophils (right) in the BAL on day 7 of 0.3LD50 dose PR8 influenza infection of Il1rnfl/flFoxp3ERT2Cre mice treated with either tamoxifen (maroon, n = 10) or oil as indicated (grey, n = 9). (i) mRNA levels of Il1rn in the indicated cell types sorted from the lungs of Il1rnfl/fl littermate controls (grey, n = 3) and Il1rnfl/flFoxp3YFPCre (orange, n = 2) infected with 0.3LD50 dose PR8 influenza. (j) mRNA levels of Il1rn in the indicated cell types sorted from the lungs of day 7 infected Il1rnfl/fl littermate controls (grey, n = 3) and Il1rnfl/flLysMCre (purple, n = 3) infected with 0.3LD50 dose PR8 influenza. (k) Foxp3YFPCre controls (white, n = 14), Il1rl1fl/fl littermate controls (gray, n = 9) and Il1rl1lfl/flFoxp3YFPCre (blue n = 7) mice were infected with 0.3LD50 dose PR8 influenza and administered i.p. and i.n. PBS diluent and another group of Il1rl1lfl/flFoxp3YFPCre mice were treated with i.p. and i.n. IL-1Ra (blue/orange, n = 5) and harvested on day 5 post infection to determine the total number (top) and percentage (bottom) of neutrophils in the BAL. Unless otherwise indicated, data are pooled from 2-3 experiments. Each dot represents one mouse, except for experiments (i and j) where each dot represents the pooled mean from an experiment. Statistics for (a-b) were calculated by unpaired t-test with Holm-Sidak adjustment for multiple comparisons. Statistics for (d-f, h, j) were calculated by unpaired Student’s t-test. Statistics for (c, g, k) were calculated by ordinary one-way ANOVA with Tukey’s multiple comparisons. (i) was calculated by two-way ANOVA with Sidak′s multiple comparisons test. Column Plots: mean with Standard Deviation. Box and whiskers plots: whiskers are max and min, box 25–75 percentile and line is median. Fold difference between groups is indicated by ×. P values are indicated in plots.

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Extended Data Fig. 9 IL-1 may mediate innate inflammatory responses to influenza via IL-1R1-expressing fibroblasts.

(a-b) Il1rl1fl/flFoxp3YFPCre (blue circles day 5 n = 7, day 7 n = 9, day 9 n = 13, day 11 n = 3), Il1rl1fl/flFoxp3YFPCreIl1a/b−/− (blue and olive circles, day 5 n = 11, day 7 n = 7, day 9 n = 9, day 11 n = 4), and Il1a/b−/− (olive circles, day 5 n = 6, day 7 n = 5, day 9 n = 3, day 11 n = 3) and Foxp3YFPCre control (white circles, day 5 n = 7, day 7 n = 14, day 9 n = 16, day 11 n = 5) mice were infected with 0.3LD50 dose PR8 influenza. (a) Total number of CD11b+Ly6G+ neutrophils in the BAL on the indicated day. (b) Total number of SiglecF+CD11clo eosinophils in the BAL on the indicated day. (c) Total number of IL-17+ γδ T cells in the lungs on day 5 of influenza infection (Foxp3YFPCre n = 7, Il1rl1fl/flFoxp3YFPCre n = 7, Il1rl1fl/flFoxp3YFPCreIl1a/b−/− n = 9). (d) Representative flow cytometry (left) and total number (right) of IL-5+- and IL 13-producing ILC2s (CD45+Thy1.2+Lin−CD3−CD4−ST2+) in the lungs on day 7 of influenza infection (Foxp3YFPCre n = 6, Il1rl1fl/fl n = 8, Il1rl1fl/flFoxp3YFPCre n = 5, Il1rl1fl/flFoxp3YFPCreIl1a/b−/− n = 6, and Il1a/b−/− n = 5). (e) Influenza NP RNA levels (copies per ng RNA) in the lungs on day 7 of influenza infection (n = 5–20 mice per group as represented by dots). (f) Bubble plot of the indicated gene expression of reanalyzed scRNA-Seq dataset clusters from CD45− lung mesenchymal cells derived from Dalghren et al. (GEO accession GSE125492)36 and Tsukui et al. (GEO accession GSE132771)37 from the indicated cell clusters shown in Fig. 8d. (g) Cell sorting strategy to isolate lung CD45−CD31−EpCAM+ epithelial cells, CD45−EpCAM−CD31+ endothelial cells, CD45−PDGFRa+PDPN+Ly6C-SCA1− fibroblasts and CD45−PDGFRa+PDPN+Ly6C+SCA1+ adventitial fibroblasts. (h) Representative expression and Geometric mean MFI of IL-1R1 expression on CD45−EpCAM−CD31+ endothelial cells, CD45−CD31−EpCAM+ epithelial cells and CD45−PDGFRa+PDPN+ fibroblasts isolated from the lungs of naïve mice (n = 4 in this representative experiment of 2 performed). (i) Fibroblasts were isolated from the lungs of naïve mice and stimulated with either control media or 10ng/ml IL-1β for 6hrs and then the expression of the indicated genes were analyzed using RT–qPCR (replicates, n = 4). Unless otherwise indicated, data are pooled from 2-3 experiments. For (a-e) and (h) each dot represents one mouse. Statistics for (a-b) were calculated by unpaired t-test with Holm-Sidak adjustment for multiple comparisons. Statistics for (c-e, h) were calculated by ordinary one-way ANOVA with Tukey’s multiple comparisons. (i) was calculated by unpaired students t-test. Column Plots: mean with Standard Deviation. Box and whiskers plots: whiskers are max and min, box 25–75 percentile and line is median. Fold difference between groups is indicated by ×. P values are indicated in plots.

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Griffith, J.W., Faustino, L.D., Cottrell, V.I. et al. Regulatory T cell-derived IL-1Ra suppresses the innate response to respiratory viral infection. Nat Immunol 24, 2091–2107 (2023). https://doi.org/10.1038/s41590-023-01655-2

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