The diversity of regulatory T (Treg) cells in health and in disease remains unclear. Individuals with colorectal cancer harbor a subpopulation of RORγt+ Treg cells with elevated expression of β-catenin and pro-inflammatory properties. Here we show progressive expansion of RORγt+ Treg cells in individuals with inflammatory bowel disease during inflammation and early dysplasia. Activating Wnt–β-catenin signaling in human and murine Treg cells was sufficient to recapitulate the disease-associated increase in the frequency of RORγt+ Treg cells coexpressing multiple pro-inflammatory cytokines. Binding of the β-catenin interacting partner, TCF-1, to DNA overlapped with Foxp3 binding at enhancer sites of pro-inflammatory pathway genes. Sustained Wnt–β-catenin activation induced newly accessible chromatin sites in these genes and upregulated their expression. These findings indicate that TCF-1 and Foxp3 together limit the expression of pro-inflammatory genes in Treg cells. Activation of β-catenin signaling interferes with this function and promotes the disease-associated RORγt+ Treg phenotype.
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RNA-seq, ChIP–seq and ATAC-seq datasets have been deposited in the Gene Expression Omnibus under accession code GSE139960. All raw data and source data that support the findings of this study are available from the corresponding authors upon request.
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We thank clinical research coordinators B. Putz and A. Duong for facilitating the patient sample supply, S. Keerthivasan for introducing relevant mouse strains to the laboratory, and M. -L. Alegre for helpful advice on the manuscript. We also want to thank the Flow Cytometry Core (UCFlow), Human Tissue Resource Center and the Animal Resources Center at the University of Chicago. This work was supported by National Institutes of Health (NIH) grants R21AI076720 and R01AI147652, a Digestive Diseases Research Core Center pilot award (NIDDK P30DK42086) and an ASH bridge grant (to F.G.), and grants R01AI108682 (to F.G. and K.K.) and R01CA160436 (to K.K). Further support came from the Praespero autoimmunity fund (to F.G. and K.K.) and the Chicago Biomedical Consortium (to F.G.). A.O.E. was supported by an NIH minority supplement. P.S.M. was supported by T32 HL07605 Institutional NRSA and is currently an LLS fellow. J.Q. was supported by an AAI Careers in Immunology Fellowship. M.O. is a T32HD007009 award recipient.
The authors declare no competing interests.
Peer review information Nature Immunology thanks Vincenzo Bronte and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available. L. A. Dempsey was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Extended Data Fig. 1 RORγt+ Treg cells producing pro-inflammatory cytokines expand in the PB/colonic mucosa of IBD patients.
Flow cytometric gating scheme to identify Treg cells in PB a. Live CD3+CD4+CD25+ Foxp3+ cells were assessed for CD127 expression and CD127−CD3+CD4+CD25+Foxp3+ Treg cells were gated for the analyses in b-f. b. Dotplots of RORγt versus CD4 expression in PB Treg cells of representative HD (HD21), and IBD (IMB29), and IBD/Dys (IMB17) patients c. Relative frequencies of RORγt+ cells within PB Treg cells. d. Representative β-catenin expression in RORγt+/RORγt− PB Treg cells. e. Cumulative β-catenin expression in RORγt+/RORγt− PB Treg cells (MFI). f. IL-17, IFN-γ, and TNF production in RORγt+ PB Treg cells before and after stimulation by PMA/ionomycin as indicated. b-f. two-sided unpaired t-test. Number of samples in c,e,f. HD(n = 16), IBD(n = 15), IBD_Dys(n = 17) g. Flow cytometric gating scheme assessing pro-inflammatory cytokine production by RORγt+ and RORγt− PB Treg populations (CD127−CD3+CD4+CD25+Foxp3+) after PMA/ionomycin stimulation. h. (left) Flow cytometric gating scheme for assessing pro-inflammatory cytokine production versus Helios expression in PB Treg cells, (right) Cumulative frequencies of Helios+ Treg cells in HD(n = 5), IBD(n = 5) and IBD/Dys(n = 4) patients, and IL-17, IFN-γ, and TNF expression in Helios+ and Helios− PB Treg cells of the same samples (two-sided unpaired t-test). i. Flow cytometric gating scheme for assessing IL-17 production by CD3+CD4+Foxp3+ RORγt+ and RORγT− colonic mucosa Treg cells.
Extended Data Fig. 2 The expression of Th17 and Treg cell signature genes in the TCGA CRC dataset indicate a prognostic relevance.
a–d. Analysis of the TCGA CRC cohort: a. Spearman correlation of average z-scores for the Th17_UP versus Treg_UP (blue, r = 0.7836, p < 0.001) signatures in CRC patients (n = 524). b. Ridge regression regularization and, c. cross validation of the deployed Cox proportional-hazards regression on the CRC clinical data extracted from TCGA. d. Histogram of Th17 gene-based score distribution through the CRC patient cohort (median = −0.033). If not stated differently data are represented as median + /− SEM and statistical testing is depicted as *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001.
Extended Data Fig. 3 tSNE projection of flow cytometric data identifies unique populations within RORγt+ Treg cells in the APC/DSS IBD-associated CRC model.
Strategy for tSNE projection of a, splenic and b, colon-tissue resident Treg populations exemplarily shown for the activation marker flow-cytometric panel: Treg populations (gated on as live/dead stain negative, CD4+CD8−Foxp3+) from all samples of all treatment groups were concatenated into one fcs file and the tSNE analysis was performed on the concatenated file (settings used for FlowJo tSNE Plugin Tool: Iterations = 1000, Perplexity = 30, ETA/Learning Rate = 100). RORγt positive and negative fractions of Treg cells are indicated in red and green in the tSNE landscapes, respectively. Different RORγt+ Treg populations were identified within in the tSNE plot and histogram expression profiles of identified RORγt+ Treg populations are shown.
Extended Data Fig. 4 Treg cell specific up-regulation of β-catenin leads to a severe scurfy-like phenotype in mice.
a, Kaplan-Mayer survival curve of Foxp3Cre(0/+) wild-type (Cre) and Foxp3Cre(0/+) Ctnnb1fl(ex3) (CAT) male mice. b, Representative picture of the scurfy-like phenotype of a CAT mouse compared to a Cre mouse (26 d old). c, Representative picture of the pathologic enlargement of peripheral LNs and splenomegaly in a CAT mouse compared to a Cre litter mate control mouse. d, H&E-stainings of paraffin sections from organs of a representative 21 d old male CAT mouse and a Cre litter mate. Enlargement of secondary lymphoid organs (SPL – spleen & pLNs – peripheral lymph nodes) and reduction of the thymic cortex (THY – thymus, arrows) in CAT mice. CAT mice show severe immune infiltrates in lung and liver (middle panels, arrows), and eosinophil infiltration in the small intestine (SI) and colon (arrows). Size are provided in the images. At least 4 independent CAT and Cre litter mate mice were analysed. e, Frequency of CD3+, CD3+CD4+, and CD3+CD8+ T cell numbers in peripheral lymphoid organs of 3-4 weeks old Cre and CAT mice as determined by flow cytometric analysis. Cre_SPL(n = 7), Cre_mLN(n = 7), Cre_pLN(n = 7), CAT_SPL(n = 10), CAT_mLN(n = 8), p(CAT_mLN)=10, data are represented as median + /− SEM and statistical testing is depicted as two-sided unpaired t-tests with *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001.
Extended Data Fig. 5 Treg cell specific stabilization of β-catenin results in severe systemic T cell activation and an altered Treg cell phenotype.
Activation status of a, CD3+CD4+ conventional T cells and, b, CD3+CD8+ CTLs was assessed via flow cytometric staining for CD25, CD44, CD69, CD62L, and Ki67 in peripheral lymphoid organs of 3-4 weeks old Foxp3Cre(0/+) wild-type (Cre) and Foxp3Cre(0/+) Ctnnb1fl(ex3) (CAT) male mice (CAT(n = 5), WT(n = 5)). c, Frequencies of total Treg cells within viable cells in peripheral lymphoid organs and the thymus (Cre_SPL(n = 5), Cre_mLN(n = 5), Cre_pLN(n = 5), Cre_THY(n = 5), CAT_SPL(n = 10), CAT_mLN(n = 10), CAT_pLN(n = 10), CAT_THY(n = 5)). d, Expression of Neuropilin in Cre and CAT Treg cells depicted as representative flow plots and cumulative column plots throughout peripheral lymphoid organs (Cre_SPL(n = 5), Cre_mLN(n = 5), Cre_pLN(n = 5), CAT_SPL(n = 4), CAT_mLN(n = 3), CAT_THY(n = 5)). Data are represented as median + /− SEM and statistical testing is depicted as two-sided unpaired t-tests with *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001.
a, Representative histograms for flow cytometric characterization of CCR9 expression in the natural chimera female heterozygote CD3+CD4+CD25+Foxp4+ Treg cells comparing YFP+ (Cre+) to YFP− (Cre−) populations in Foxp3Cre(+/−) Ctnnb1fl(ex3) (CAT) and Foxp3Cre(+/−) (Cre) chimeras in MLN and Spleen, as indicated. (FMO = fluorescence minus one negative staining control). b, Quantification of CCR9 MFI respresented as bar graphs in MLN (Cre(n = 5), CAT(n = 5)). Data are represented as median + /− SEM and statistical testing is depicted as one way Anova multiple comparisons with *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001.
Extended Data Fig. 7 TCF-1 binds gene loci that are involved in T cell activation and survival in wild-type Treg cells.
a, Pie chart of the distribution of TCF-1 binding in genomic regions (P = promoter, PE = poised enhancer, AE = active enhancer) identified by K-means-clustering. Peak numbers (p), corresponding gene numbers (g), and relative percentages (%) for each genomic region. b, Heat maps centered on TCF-1 binding in indicated genomic regions (± 1.5 kb) and enrichment of histone marks (H3K4me1, H3K4me3, H3K27me3, H3K27Ac), chromatin accessibility (ATAC), and DNA methylation (MBD). c, Enrichment histograms of TCF-1 binding, histone marks, chromatin accessibility, and DNA methylation marks at TCF-1 bound sites (± 1.5 kb) in the indicated genomic regions. d, De novo transcription-factor-binding motif analysis (HOMER) of TCF-1-bound sites for the indicated genomic regions. Most, significantly enriched motifs and corresponding p values are listed. e, Functional pathways enriched for TCF-1-bound genes in the indicated genomic regions. Pathways and statistical enrichment were determined using Metascape (http://www.metascape.org).
Extended Data Fig. 8 Foxp3 preferentially binds accessible chromatin and its consensus motif within different regulatory elements of genes in Treg cells.
a, Pie chart of the distribution of Foxp3 binding in genomic regions (P = promoter, PE = poised enhancer, AE = active enhancer) identified by K-means-clustering. Peak numbers (p), corresponding gene numbers (g), and relative percentages (%) for each genomic region. b, Heat maps centered on Foxp3 binding in indicated genomic regions (± 1.5 kb) and enrichment of histone marks (H3K4me1, H3K4me3, H3K27me3, H3K27Ac), chromatin accessibility (ATAC), and DNA methylation (MBD). c, Enrichment histograms of Foxp3 binding, histone marks, chromatin accessibility, and DNA methylation marks at Foxp3 bound sites (± 1.5 kb) in the indicated genomic regions. d, De novo transcription-factor-binding motif analysis (HOMER) of TCF-1-bound sites for the indicated genomic regions. Most, significantly enriched motifs and corresponding p values are listed. e, Functional pathways enriched for TCF-1-bound genes in the indicated genomic regions. Pathways and statistical enrichment were determined using Metascape (http://www.metascape.org).
Extended Data Fig. 9 Wnt/β-catenin activation does not significantly alter the Treg_UP signature and enhances the expression of leukocyte migration signature genes in Treg cells.
RNA expression heat maps (n = 3 biological replicates for each genotype, FPKMs) showing genes of GSEA analysis for the Treg_UP, TH17_UP, and leukocyte migration signature displayed in Fig. 8d of CAT versus Cre Treg cells.
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Quandt, J., Arnovitz, S., Haghi, L. et al. Wnt–β-catenin activation epigenetically reprograms Treg cells in inflammatory bowel disease and dysplastic progression. Nat Immunol 22, 471–484 (2021). https://doi.org/10.1038/s41590-021-00889-2
Nature Immunology (2021)