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

Nature Immunology volume 22, pages 1152–1162 (2021)Cite this article

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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.

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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.

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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.

Author information

Author notes

  1. These authors contributed equally: Abu Osman, Bingyu Yan.

  2. These authors jointly supervised this work: Majid Kazemian, Fotini Gounari, Khashayarsha Khazaie.

Authors and Affiliations

  1. Department of Immunology, Mayo Clinic, Rochester, MN, USA

    Abu Osman, Kevin D. Pavelko, Abdulrahman Saadalla, Mahendra Pal Singh & Khashayarsha Khazaie

  2. Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, IL, USA

    Abu Osman, Jasmine Quandt & Fotini Gounari

  3. Department of Biochemistry, Purdue University, Purdue, IN, USA

    Bingyu Yan & Majid Kazemian

  4. Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA

    Ying Li

  5. Department of Computer Science, Purdue University, Purdue, IN, USA

    Majid Kazemian

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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.

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Correspondence to Majid Kazemian, Fotini Gounari or Khashayarsha Khazaie.

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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.

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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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