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IL-1 signaling modulates activation of STAT transcription factors to antagonize retinoic acid signaling and control the TH17 cell–iTreg cell balance

Abstract

Interleukin 17 (IL-17)-producing helper T cells (TH17 cells) and CD4+ inducible regulatory T cells (iTreg cells) emerge from an overlapping developmental program. In the intestines, the vitamin A metabolite retinoic acid (RA) is produced at steady state and acts as an important cofactor to induce iTreg cell development while potently inhibiting TH17 cell development. Here we found that IL-1 was needed to fully override RA-mediated expression of the transcription factor Foxp3 and induce protective TH17 cell responses. By repressing expression of the negative regulator SOCS3 dependent on the transcription factor NF-κB, IL-1 increased the amplitude and duration of phosphorylation of the transcription factor STAT3 induced by TH17-polarizing cytokines, which led to an altered balance in the binding of STAT3 and STAT5 to shared consensus sequences in developing T cells. Thus, IL-1 signaling modulated STAT activation downstream of cytokine receptors differently to control the TH17 cell–iTreg cell developmental fate.

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Figure 1: IL-1β counteracts the RA-dependent inhibition of TH17 cell development.
Figure 2: IL-1R signaling is required for the host-protective TH17 and TH17 cell–iTreg cell balance in vivo.
Figure 3: In the absence of IL-1β, in vivo blockade of RA facilitates the iTreg cell–to–TH17 cell conversion during enteropathogenic bacterial infection.
Figure 4: IL-1β counteracts RA-driven, IL-2- and STAT5-dependent repression of TH17 cell development.
Figure 5: NF-κB-dependent repression of SOCS3 by IL-1β enhances the amplitude and duration of STAT3 phosphorylation.
Figure 6: Deletion of SOCS3 abrogates the IL-1-dependent reversal of RA's repression of TH17 cell development.
Figure 7: IL-1β reverses the RA-mediated binding of STAT5 to the Il17a-Il17f and Foxp3 loci.

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Acknowledgements

We thank H. Qin, L. Xu and members of the Weaver laboratory for advice and comments; G. Frankel and S. Wiles (Imperial College, London) for the bioluminescent C. rodentium strain; T. DeSilva (University of Alabama at Birmingham) for Rosa26TdTomato fl/+ mice; D. O'Quinn for assistance with bioluminiscent imaging; B.J. Parsons for technical assistance; G. Gaskins for editorial assistance; the University of Alabama at Birmingham Small Animal Imaging Facility for imaging studies; the University of Alabama at Birmingham Center for AIDS Research Flow Cytometry Core for sorting cells by flow cytometry; and the University of Alabama at Birmingham Epitope Recognition and Immunoreagent Core Facility for antibody preparation. Supported by the US National Institutes of Health (PO1DK71176 and R01DK093015 to C.T.W. and R.D.H., and R01AI047833 to W.S.P.) and the Crohn's and Colitis Foundation of America (C.T.W. and R.B.).

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Authors and Affiliations

Authors

Contributions

R.B., S.K.W., R.D.H. and C.T.W. designed the studies; R.B., S.K.W., S.B. and R.D.H. performed the experiments; C.L.Z. advised on design and execution of figures; T.R.S. performed analyses of pathology; E.N.B. assisted in the design and interpretation of studies involving SOCS3; W.S.P. provided TAT-Cre peptide and provided guidance on its use in naive CD4+ T cells; and R.B., S.K.W. and C.T.W. wrote and edited the manuscript.

Corresponding author

Correspondence to Casey T Weaver.

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Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Effects of IL-1β on expression of RA and IL-1 receptor components.

(a,b) FACS-sorted naïve CD4 T cells (CD4+CD25CD62Lhigh CD44low) from Il17fThy-1.1 mice were activated with plate-bound αCD3 and soluble αCD28 under Th17 polarizing conditions in presence or absence of IL-1β under indicated concentrations of at-RA (1 nM-10 – 100nM). Cells were collected at 60 h for analysis by RT-PCR for expression levels of Rara,b,g (above) and Rxra,b,g (below) transcripts (a) and for expression levels of Il1r1, Ilrap and Il1r2 transcripts (b). Values are normalized to Th0 controls. Data are representative of two independent experiments and six samples (n=6) (means and s.e.m. in a,b). *p<0.05, **p<0.01 (two-tailed unpaired T-test).

Supplementary Figure 2 IL-17-expressing cells and IL-1 signaling are required for host protection during infection with Citrobacter rodentium.

(a) Histopathology of distal colonic tissues from untreated Il17f Thy-1.1 mice, Il17f Thy-1.1 mice treated with depleting anti-Thy1.1 mAb or Il1r1–/– mice collected eight days post inoculation with 2 × 109 cfu C. rodentium. H&E-stained sections (scale bars: 100 μm). (b) Histopathological scoring of distal colons from groups in a was performed at d8 PI as described in Materials and Methods. (c) ELISA quantitation of IL-22 in supernatants from homogenates of colonic tissue collected from Il17f Thy-1.1 and Il1r1–/– mice at the indicated times after inoculation with C. rodentium and cultured ex vivo for 24 hours. (d) Schematic representation of experiment in Main Fig. 2e,f . Data are representative of one of two similar experiments (a,b) or two independent experiments with 6 mice per group (b,c) (means and s.e.m.). *p<0.05, **P<0.01 (two-tailed unpaired T-test).

Supplementary Figure 3 IL-1 receptor deficiency alters the balance of Foxp3- and IL-17-expressing T cells during enteropathogenic bacterial infection.

(a) WT B6 mice were inoculated with C. rodentium (2 x 109 cfu) and assessed for frequencies of CD4+Foxp3+ lymphocytes in MLN and LP at indicated time-points post-infection by flow cytometry (CD4 T cell gate). (b) Pooled data from a showing frequencies of CD4+Foxp3+ lymphocytes in MLN and colonic LP at indicated time-points post-infection. (c) Il1r1+/+ Il17f Thy-1.1.Foxp3gfp and Il1r1–/– Il17f Thy-1.1.Foxp3gfp mice were inoculated with 2 x 109 cfu C. rodentium and analyzed without restimulation ex vivo for frequencies of IL-17F (Thy1.1+) and Foxp3 (GFP+) CD4+ T cells within the activated pool of T cells isolated from colonic lamina propria (LP) at indicated time-points post-infection. Numbers are percentages of cells in the each quadrant. (d) Pooled data from c showing frequencies of IL-17F (Thy1.1+) and Foxp3 (GFP+) isolated from colonic LP T cells at indicated time points post-infection. Data are representative of one of two similar experiments (a,c) or two independent experiments with 6 or more mice per group as depicted by individual data points corresponding to one mouse (b,d) (means and s.e.m.). *p<0.05, **p<0.01 (two-tailed unpaired T-test). (e) Schematic representation of experiment in Main Fig. 3a,b .

Supplementary Figure 4 In vivo blockade of RA-mediated signaling reduces intestinal bacterial load in the absence of IL-1 signaling.

(a) Serial whole-body imaging of Il1r1+/+ Il17f Thy-1.1.Foxp3gfp and Il1r1–/– Il17f Thy-1.1 1.Foxp3gfp mice inoculated with 2 x 109 cfu C. rodentium and gavaged with vehicle alone or with retinoic acid inhibitor (LE135) on days 3-7 post infection and imaged at the indicated days post infection. (b) Colonization kinetics data from a. (c) Body weight kinetics of Il1r1+/+ Il17f Thy-1.1 1.Foxp3gfp and Il1r1–/– Il17f Thy-1.1 1.Foxp3gfp mice inoculated with C. rodentium and gavaged with vehicle alone or with retinoic acid inhibitor (LE135) on indicated days post infection. Data are representative of one of two similar experiments (a) or two independent experiments with 6 mice per group (b, c) (means and s.e.m.). *p<0.05 (Il1r1+/+ vs Il1r1–/–); #p<0.05 (Il1r1–/– + Vehicle vs Il1r1–/– + LE135); **p<0.01 (Il1r1+/+ vs Il1r1–/–) (two-tailed unpaired T-test).

Supplementary Figure 5 IL-1, but not IL-23, overrides RA-mediated repression of TH17 development.

(a) FACS-sorted naïve CD4+ T cells from Il17f Thy-1.1 1 mice were activated with plate-bound αCD3 and soluble αCD28 under Th17 polarizing conditions, with or without addition of IL-1β (20 ng/ml) or RA (1 nM). Cells recovered at day 3-4 were stained for surface CD4 and IL-17F (Thy1.1) and intracellular Foxp3 and analyzed by flow cytometry. Numbers are percentages of cells in the each quadrant. (b) Naïve CD4+ T cells from Il17f Thy-1.1 mice were activated under Th17 conditions as above with or without IL-1β or IL-23. Cells recovered at day 5 were stained for surface expression of CD4 and Thy1.1 (IL-17F) and intracellular expression of IL-17A, IFN-γ and Foxp3 and analyzed by flow cytometry. Numbers are percentages of cells in the each quadrant. (c) Pooled data from b, including pooled frequencies of IFN-γ+ cells, showing frequencies of cells expressing indicated cytokines or Foxp3. Data are representative of one of three similar experiments (a,b) or three independent experiments with 6 samples per group in c (means and s.e.m. in c). **p<0.01 (two-tailed unpaired T-test).

Supplementary Figure 6 IL-1 increases IL-21-mediated tyrosine-phosphorylation of STAT3 in TH17 cells.

(a) Naïve CD4+ T cells were cultured under Th17 polarizing conditions for 4 days, then restimulated with IL-21 alone, IL-1β alone, or both for the indicated time periods. Cell lysates were harvested, immunoblotted with antibody directed against phospho-tyrosine(705)-STAT3 (pY-STAT3; upper panel) or total STAT3 (lower panel). (b) Pooled data representing integrated band density values (IDVs) of pY-STAT3 normalized to total STAT3 from a. Data are representative of one of two independent experiments (a) or are pooled from two independent experiments representing integrated band density values (IDVs) of pY-STAT3 normalized to total STAT3 from a (means and s.e.m. in b). *p<0.05 (two-tailed unpaired T-test).

Supplementary Figure 7 Comparative effects of inhibitors of the NF-κB and mitogen-activated protein kinase pathways on IL-1-induced augmentation of the tyrosine- and serine-phosphorylation of STAT3.

(a) Naïve CD4+ T cells were cultured under Th17 polarizing conditions for 5 days, then restimulated with IL-23 alone, IL-1β alone, or both for indicated time periods. Cell lysates were harvested, immunoblotted with antibody directed against phospho-serine(727)-STAT3 (pS-STAT3), with anti-STAT3 serving as a loading control. (b,c) Naïve CD4+ T cells polarized as in a were isolated and pre-treated with nothing or the indicated signaling inhibitors for 1 hour, then either left unstimulated or treated with IL-23 +/- IL-1β before cell lysates were harvested and immunoblotted for pS727-STAT3 (b), pY705-STAT3 (c), or a STAT3 loading control (b,c). Phospho-STAT integrated band density values (IDVs) were normalized to total STAT3 and expressed as fold change over unstimulated cells. Data are representative of one of two independent experiments (a) or are pooled from two independent experiment (b,c) (means and s.e.m.). *p<0.05, **p<0.01 (two-tailed unpaired T test).

Supplementary Figure 8 IL-1β and IL-6 are required for the developmental plasticity of Foxp3+ iTreg cells.

(a) FACS-sorted naïve CD4 T cells (CD4+CD25-CD62Lhigh CD44low) from WT B6 mice were activated with plate-bound αCD3 and soluble αCD28 under Treg polarizing conditions in presence or absence of IL-23 or IL-1β and analyzed for intracellular Foxp3 and IL-17A. (b) Pooled data from a. (c) FACS-sorted naïve CD4+ T cells from Il17f Thy-1.1.Foxp3gfp mice were activated with plate-bound αCD3 and soluble αCD28 under Treg polarizing conditions. On day 4 of primary culture the Thy1.1-GFP+ fraction of cells were sorted by flow cytometry and further cultured under Th17 conditions with or without IL-1β (20ng/ml), in the presence or absence of at-RA (1nM). On day 4 of secondary culture, frequencies of IL-17F (Thy1.1) versus Foxp3-GFP+ cells were determined after surface staining of Thy1.1 (IL-17F) and flow cytometry. Numbers are percentages of cells in the each quadrant. (d) Pooled data from secondary cultures from c. Data are: representative of one of two similar independent experiments a; pooled from two independent experiments with 6 samples per group b; one of two similar independent experiments c; or pooled from two independent experiments with 6 samples per group where individual data points depict each sample d (means and s.e.m. in b,d). **p<0.01 (two-tailed unpaired T-test).

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Basu, R., Whitley, S., Bhaumik, S. et al. IL-1 signaling modulates activation of STAT transcription factors to antagonize retinoic acid signaling and control the TH17 cell–iTreg cell balance. Nat Immunol 16, 286–295 (2015). https://doi.org/10.1038/ni.3099

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