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TCF-1 controls Treg cell functions that regulate inflammation, CD8+ T cell cytotoxicity and severity of colon cancer

Abstract

The transcription factor TCF-1 is essential for the development and function of regulatory T (Treg) cells; however, its function is poorly understood. Here, we show that TCF-1 primarily suppresses transcription of genes that are co-bound by Foxp3. Single-cell RNA-sequencing analysis identified effector memory T cells and central memory Treg cells with differential expression of Klf2 and memory and activation markers. TCF-1 deficiency did not change the core Treg cell transcriptional signature, but promoted alternative signaling pathways whereby Treg cells became activated and gained gut-homing properties and characteristics of the TH17 subset of helper T cells. TCF-1-deficient Treg cells strongly suppressed T cell proliferation and cytotoxicity, but were compromised in controlling CD4+ T cell polarization and inflammation. In mice with polyposis, Treg cell–specific TCF-1 deficiency promoted tumor growth. Consistently, tumor-infiltrating Treg cells of patients with colorectal cancer showed lower TCF-1 expression and increased TH17 expression signatures compared to adjacent normal tissue and circulating T cells. Thus, Treg cell–specific TCF-1 expression differentially regulates TH17-mediated inflammation and T cell cytotoxicity, and can determine colorectal cancer outcome.

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Fig. 1: TCF-1 deficiency selectively reprograms Treg cells without compromising their core signature.
Fig. 2: Cumulative data from FACS analysis shows activation and expansion of Treg cells and CD4+ Tconv cells in TCF-1-deficient mice.
Fig. 3: Single-cell transcriptomics delineates distinct Treg subpopulations in the mesenteric lymph nodes.
Fig. 4: TCF-1-deficient and TCF-1-sufficient Treg cells show distinct effector functions.
Fig. 5: TCF-1-deficient Treg cells suppress viral antigen–specific CD8+ T cell cytotoxicity and T cell proliferation.
Fig. 6: TCF-1-deficient Treg cells fail to suppress TH1 or TH17 polarization of CD4+ Tconv cells.
Fig. 7: TCF-1-deficient Treg cells promote inflammation and tumor growth in polyposis-prone APCΔ468 mice.
Fig. 8: TCF7 is downregulated in CRC tumor-infiltrating Treg cells.

Data availability

The bulk RNA-seq and scRNA-seq datasets are deposited in the Gene Expression Omnibus under accession GSE163084. Source data are provided with this paper.

Code availability

The codes used for bulk RNA-seq and scRNA-seq analysis followed typical pipelines from public R packages (DESeq2 and Seurat). All codes are available upon request.

References

  1. 1.

    Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).

    CAS  PubMed  Google Scholar 

  2. 2.

    Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    CAS  PubMed  Google Scholar 

  3. 3.

    Khattri, R., Cox, T., Yasayko, S. A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4, 337–342 (2003).

    CAS  PubMed  Google Scholar 

  4. 4.

    Benoist, C. & Mathis, D. Treg cells, life history and diversity. Cold Spring Harb. Perspect. Biol. 4, a007021 (2012).

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Ohnmacht, C. et al. The microbiota regulates type 2 immunity through RORγt+ T cells. Science 349, 989–993 (2015).

    CAS  PubMed  Google Scholar 

  6. 6.

    Schiering, C. et al. The alarmin IL-33 promotes regulatory T cell function in the intestine. Nature 513, 564–568 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Pratama, A., Schnell, A., Mathis, D. & Benoist, C. Developmental and cellular age direct conversion of CD4+T cells into RORγ+ or Helios+ colon Treg cells.J. Exp. Med. 217, e20190428 (2020).

    PubMed  Google Scholar 

  8. 8.

    Zhou, J., Nefedova, Y., Lei, A. & Gabrilovich, D. Neutrophils and PMN-MDSC: their biological role and interaction with stromal cells. Semin. Immunol. 35, 19–28 (2018).

    CAS  PubMed  Google Scholar 

  9. 9.

    Blatner, N. R. et al. Expression of RORγt marks a pathogenic regulatory T cell subset in human colon cancer. Sci. Transl. Med. 4, 164ra159 (2012).

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Miragaia, R. J. et al. Single-cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation. Immunity 50, 493–504 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Blatner, N. R. et al. In colorectal cancer mast cells contribute to systemic regulatory T cell dysfunction. Proc. Natl Acad. Sci. USA 107, 6430–6435 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Gounaris, E. et al. T regulatory cells shift from a protective anti-inflammatory to a cancer-promoting proinflammatory phenotype in polyposis. Cancer Res. 69, 5490–5497 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Keerthivasan, S. et al. β-Catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T cells. Sci. Transl. Med. 6, 225ra228 (2014).

    Google Scholar 

  14. 14.

    Quandt, J. et al. Wnt–β-catenin activation epigenetically reprograms Treg cells in inflammatory bowel disease and dysplastic progression. Nat. Immunol. 22, 471–484 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Sumida, T. et al. Activated β-catenin in Foxp3+ regulatory T cells links inflammatory environments to autoimmunity. Nat. Immunol. 19, 1391–1402 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Mosimann, C., Hausmann, G. & Basler, K. β-catenin hits chromatin: regulation of Wnt target gene activation. Nat. Rev. Mol. Cell Biol. 10, 276–286 (2009).

    CAS  PubMed  Google Scholar 

  17. 17.

    Barra, M. M., Richards, D. M., Hofer, A. C., Delacher, M. & Feuerer, M. Premature expression of Foxp3 in double-negative thymocytes. PLoS ONE 10, e0127038 (2015).

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Barra, M. M. et al. Transcription factor 7 limits regulatory T cell generation in the thymus. J. Immunol. 195, 3058–3070 (2015).

    CAS  PubMed  Google Scholar 

  19. 19.

    van Loosdregt, J. et al. Canonical Wnt signaling negatively modulates regulatory T cell function. Immunity 39, 298–310 (2013).

    PubMed  Google Scholar 

  20. 20.

    Xing, S. et al. Tcf1 and Lef1 are required for the immunosuppressive function of regulatory T cells. J. Exp. Med. 216, 847–866 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Mielke, L. A. et al. TCF-1 limits the formation of Tc17 cells via repression of the MAF–RORγt axis. J. Exp. Med. 216, 1682–1699 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Emmanuel, A. O. et al. TCF-1 and HEB cooperate to establish the epigenetic and transcription profiles of CD4+CD8+ thymocytes. Nat. Immunol. 19, 1366–1378 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Rubtsov, Y. P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546–558 (2008).

    CAS  PubMed  Google Scholar 

  24. 24.

    Chapman, N. M. & Chi, H. mTOR links environmental signals to T cell fate decisions. Front Immunol. 5, 686 (2014).

    PubMed  Google Scholar 

  25. 25.

    Neumann, C. et al. c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host–microbiota homeostasis. Nat. Immunol. 20, 471–481 (2019).

    CAS  PubMed  Google Scholar 

  26. 26.

    Kim, H. J. et al. Stable inhibitory activity of regulatory T cells requires the transcription factor Helios. Science 350, 334–339 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Thornton, A. M. et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J. Immunol. 184, 3433–3441 (2010).

    CAS  PubMed  Google Scholar 

  28. 28.

    Fassett, M. S., Jiang, W., D’Alise, A. M., Mathis, D. & Benoist, C. Nuclear receptor Nr4a1 modulates both regulatory T cell differentiation and clonal deletion. Proc. Natl Acad. Sci. USA 109, 3891–3896 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Kovalovsky, D. et al. β-Catenin/Tcf determines the outcome of thymic selection in response to αβTCR signaling. J. Immunol. 183, 3873–3884 (2009).

    CAS  PubMed  Google Scholar 

  30. 30.

    Pabbisetty, S. K. et al. Peripheral tolerance can be modified by altering KLF2-regulated Treg migration. Proc. Natl Acad. Sci. USA 113, E4662–E4670 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Beischlag, T. V. et al. Recruitment of the NCoA/SRC-1/p160 family of transcriptional coactivators by the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator complex. Mol. Cell. Biol. 22, 4319–4333 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Zemmour, D. et al. Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR. Nat. Immunol. 19, 291–301 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Balderhaar, H. J. et al. The CORVET complex promotes tethering and fusion of Rab5/Vps21-positive membranes. Proc. Natl Acad. Sci. USA 110, 3823–3828 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Kolinski, T., Marek-Trzonkowska, N., Trzonkowski, P. & Siebert, J. Heat-shock proteins (HSPs) in the homeostasis of regulatory T cells. Cent. Eur. J. Immunol. 41, 317–323 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Joller, N. et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory TH1 and TH17 cell responses. Immunity 40, 569–581 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Qiu, X. B., Shao, Y. M., Miao, S. & Wang, L. The diversity of the DnaJ/Hsp40 family, the crucial partners for Hsp70 chaperones. Cell. Mol. Life Sci. 63, 2560–2570 (2006).

    CAS  PubMed  Google Scholar 

  37. 37.

    Weis, A. M., Soto, R. & Round, J. L. Commensal regulation of T cell survival through Erdr1. Gut Microbes 9, 458–464 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Miyagawa, I. et al. Induction of regulatory T cells and its regulation with insulin-like growth factor/insulin-like growth factor binding protein-4 by human mesenchymal stem cells. J. Immunol. 199, 1616–1625 (2017).

    CAS  PubMed  Google Scholar 

  39. 39.

    Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    CAS  PubMed  Google Scholar 

  40. 40.

    La Manno, G. et al. RNA velocity of single cells. Nature 560, 494–498 (2018).

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Chen, Z. et al. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc. Natl Acad. Sci. USA 103, 8137–8142 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Meixner, A., Karreth, F., Kenner, L. & Wagner, E. F. JunD regulates lymphocyte proliferation and T helper cell cytokine expression. EMBO J. 23, 1325–1335 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Woo, S. R. et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T cell function to promote tumoral immune escape. Cancer Res. 72, 917–927 (2012).

    CAS  PubMed  Google Scholar 

  44. 44.

    Chen, M. L. et al. Regulatory T cells suppress tumor-specific CD8+ T cell cytotoxicity through TGF-β signals in vivo. Proc. Natl Acad. Sci. USA 102, 419–424 (2005).

    CAS  PubMed  Google Scholar 

  45. 45.

    Fahlen, L. et al. T cells that cannot respond to TGF-β escape control by CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 737–746 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Mempel, T. R. et al. Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 25, 129–141 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Pavelko, K. D. et al. Theiler’s murine encephalomyelitis virus as a vaccine candidate for immunotherapy. PLoS ONE 6, e20217 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Esplugues, E. et al. Control of TH17 cells occurs in the small intestine. Nature 475, 514–518 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Gounaris, E. et al. Live imaging of cysteine–cathepsin activity reveals dynamics of focal inflammation, angiogenesis and polyp growth. PLoS ONE 3, e2916 (2008).

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Zhang, Y. et al. Deep single-cell RNA-sequencing data of individual T cells from treatment-naive colorectal cancer patients. Sci. Data 6, 131 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Blatner, N. R., Gounari, F. & Khazaie, K. The two faces of regulatory T cells in cancer. Oncoimmunology 2, e23852 (2013).

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Bos, P. D. & Rudensky, A. Y. Treg cells in cancer: a case of multiple personality disorder. Sci. Transl. Med. 4, 164fs144 (2012).

    Google Scholar 

  53. 53.

    Kwon, H. K., Chen, H. M., Mathis, D. & Benoist, C. Different molecular complexes that mediate transcriptional induction and repression by Foxp3. Nat. Immunol. 18, 1238–1248 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    van der Veeken, J. et al. The transcription factor Foxp3 shapes regulatory T cell identity by tuning the activity of trans-acting intermediaries. Immunity 53, 971–984 (2020).

    PubMed  Google Scholar 

  55. 55.

    Pavelko, K. D., Bell, M. P., Harrington, S. M. & Dong, H. B7-H1 influences the accumulation of virus-specific tissue resident memory T cells in the central nervous system. Front. Immunol. 8, 1532 (2017).

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411–420 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Zhou, Y. et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun. 10, 1523 (2019).

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    Tirosh, I. et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352, 189–196 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by NIH grants R01 AI 108682 (to F.G. and K.K.), RO1 AI 147652 (to F.G.) and R35GM138283 (to M.K.), and a Praespero Innovation Award Alberta, Canada (to F.G. and K.K.). N. Carapanceanu and V. Carapanceanu are thankfully acknowledged for excellent technical support. L. Pennell (BioLegend) is gratefully acknowledged for advice with scRNA-seq techniques. V. Simon (Mayo Clinic) is gratefully acknowledged for assistance with scRNA-seq. A. V. Lucs (Eli Lilly) is thankfully acknowledged for providing the TGF-βRI inhibitor LY3200882 and for scientific advice.

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Contributions

A.O. planned and performed experiments; acquired, analyzed and interpreted data; and helped with writing of the manuscript. K.D.P., J.Q., A.S. and M.P.S. performed experiments, acquired and analyzed data, and prepared figures. B.Y. and Y.L. performed scRNA-seq analysis and prepared figures, helped with the interpretation of data and writing of the manuscript. M.K., F.G. and K.K. analyzed and interpreted data, prepared figures and wrote the manuscript. K.K. conceived the project and designed and oversaw experiments.

Corresponding authors

Correspondence to Majid Kazemian or Fotini Gounari or Khashayarsha Khazaie.

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The authors declare no competing interests.

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Peer review information Nature Immunology thanks Federica Facciotti 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.

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

Extended data

Extended Data Fig. 1 TCF-1 deficiency selectively reprograms Treg-cells without compromising their core signature.

Treg-cells were isolated from the mesenteric lymph nodes of Foxp3Cre and Tcf7fl/flFoxp3Cre mice. (a) Representative FACS histograms of MLN purified cells from Foxp3Cre Tcf7fl/fl and control Foxp3Cre showing selective loss of TCF-1 from Treg-cells in Foxp3Cre Tcf7fl/fl mice. (b and c) Histogram plots showing the cumulative data of the same. (b: n = 4; p < 0.0001 & c: n = 5) Data are representative of two independent experiments and n represents biologically independent replicate mice; means ± SEM; two-sided, unpaired t-test. (d) GSEA plot comparing the enrichment of genes expressed more strongly in Foxp3Cre versus Foxp3CreTcf7fl/fl Treg-cells.

Source data

Extended Data Fig. 2 Representative FACS plots of lymphocyte surface markers expressed by Treg-cells.

Treg-cells were isolated from the mesenteric lymph nodes of Foxp3Cre and Tcf7fl/flFoxp3Cre mice. See cumulative data presented in Fig. 2. (a-c) CD4+ cells were pre-gated and frequency of CD69+, ICOS+, and PD1+ cells among CD4+FOXP3 Tcon or CD4+FOXP3+ Treg-cells was measured, as indicated. (d) CD4+ cells were pre-gated and frequency of CD44+CD62L cells among CD4+FOXP3 Tcon cells was measured. (e) CD4+ cells were pre-gated and frequency of CD4+FOXP3+ Treg-cells was measured. (f) CD4+ cells were pre-gated and frequency of FOXP3+CD25+ Treg-cells was measured. (g) CD4+FOXP3+ Treg-cells were pre-gated and frequency of RORγT+HELIOS or RORγT+HELIOS+ was measured. (h) CD4+FOXP3+ Treg-cells and frequency of CD44+CD62L cells among Treg cells was measured. Numbers inside quadrants indicate percent cells in the respective quadrants.

Extended Data Fig. 3 Treg purification.

Treg-cells were isolated from the mesenteric lymph nodes of Foxp3Cre and Tcf7fl/flFoxp3Cre mice. (a) Schematic representation of purification of Treg-cells, and FACS analysis showing over 90% purity. (b) Expression changes of the Tcf7 transcripts between TCF-1-deficient and TCF-1-sufficient Treg-cells. The color intensity is proportional to the average gene expression across cells in the indicated Treg cluster. The size of circles is proportional to percentage of cells expressing indicated genes.

Extended Data Fig. 4 Single-cell RNAseq reveals distinct Treg populations.

mRNA expression of select indicated genes projected on the UMAP. Note varied expression of Klf2 but broad and uniform expression of Izumo1r by Treg clusters, high expression of Mif, Vps8, and Ifit1 in the respective Mif (cluster 3), Vps8 (cluster 8), Ifn (cluster 9). Expression of Ccl5 is prominent in the Cd63 (cluster 7), which is likely not Treg-cells.

Extended Data Fig. 5 TCF-1-deficient and sufficient Treg-cells show distinct effector functions.

Treg-cells were isolated from the mesenteric lymph nodes of Foxp3Cre and Tcf7fl/flFoxp3Cre mice. (a) mRNA expression of Maf projected on the UMAP, comparing Treg-cells derived from Foxp3Cre to Tcf7fl/fl Foxp3Cre mice. (b) Violin plots showing expression of Maf in individual Treg clusters. (c) GSEA of MAF downregulated genes and TH17 pathway defined by Stubbington. (d) Kegg IL17 signaling pathway projected on UMAP, comparing TCF-1-sufficient and TCF-1-deficient Treg-cells (e) GSEA analysis for the Kegg IL17 signaling pathway comparing transcriptomes of TCF-1-sufficient and TCF-1-deficient Treg-cells across all cell types. Normalized enrichment scores (NES) are color coded. -log10 (FDR) values are proportional to the circle size. FDR > 15% are masked with gray color. (fgh) mRNA expression of Ccr9, Erdr1 and Igfbp4 projected on the UMAP, comparing TCF-1-sufficient and TCF-1-deficient Klf2 cells for the Kegg IL17 pathway.

Extended Data Fig. 6 Treg-cells are activated and polarized during polyposis.

Treg_cells were isolated from the mesenteric lymph nodes of WT and APCΔ486 mice. (a) UMAP projection (left panel) and fraction of cells in each cell type (stack bars; right panel) for APCΔ486 and control B6 Treg-cells. Data are from two replicates. (b) Dot plot showing the expression of Tcf7 across all cell types in ApcΔ486 and control B6 Treg-cells. Color and size of the dots are proportional to the expression level and percent of cells expressing Tcf7 in each indicated cluster. (c) Expression of Socs3, Jund, Lag3 and Maf between APCΔ486 and B6 cells projected on the UMAP. See TableS4 for the full list. The fold change in percent of cells expressing the indicated gene in each cell type is proportional to the circle size. Adjusted-p-values > 0.01 are masked with gray color. (d) Expression changes of the most differentially expressed genes between APCΔ486 and control B6 Treg-cells. See TableS4 for the full list. The fold change in expression intensities is color-coded. (e) RNA velocity vectors overlaid on UMAP for B6 (left) and APCΔ486 (right) Treg-cells.

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Source data

Source Data Fig. 2

Numerical FACS values.

Source Data Fig. 5

Numerical FACS values.

Source Data Fig. 6

Numerical FACS values.

Source Data Fig. 7

Numerical FACS values.

Source Data Extended Data Fig. 1

Numerical FACS values.

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Osman, A., Yan, B., Li, Y. et al. TCF-1 controls Treg cell functions that regulate inflammation, CD8+ T cell cytotoxicity and severity of colon cancer. Nat Immunol 22, 1152–1162 (2021). https://doi.org/10.1038/s41590-021-00987-1

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