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Stem-like T cells are associated with the pathogenesis of ulcerative colitis in humans

Abstract

To understand the role of T cells in the pathogenesis of ulcerative colitis (UC), we analyzed colonic T cells isolated from patients with UC and controls. Here we identified colonic CD4+ and CD8+ T lymphocyte subsets with gene expression profiles resembling stem-like progenitors, previously reported in several mouse models of autoimmune disease. Stem-like T cells were increased in inflamed areas compared to non-inflamed regions from the same patients. Furthermore, TCR sequence analysis indicated stem-like T cells were clonally related to proinflammatory T cells, suggesting their involvement in sustaining effectors that drive inflammation. Using an adoptive transfer colitis model in mice, we demonstrated that CD4+ T cells deficient in either BCL-6 or TCF1, transcription factors that promote T cell stemness, had decreased colon T cells and diminished pathogenicity. Our results establish a strong association between stem-like T cell populations and UC pathogenesis, highlighting the potential of targeting this population to improve clinical outcomes.

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Fig. 1: Stem-like CD4+ and CD8+ T cells were found in colonic tissue.
Fig. 2: Stem-like CD8+ T cells in inflamed tissue are related to pathogenic T cells.
Fig. 3: Stem-like CD4+ T cells were clonally related to TH17 cells through an intermediary population.
Fig. 4: BCL-6 deficiency attenuated the pathogenicity of CD4+ T cells.
Fig. 5: BCL-6 deficiency impaired TH17 and CD4+ CTL development.
Fig. 6: TCF1-deficiency attenuated pathogenicity of CD4+ T cells.
Fig. 7: TCF1-expressing stem-like mouse CD4+ T cells induced more colitis.
Fig. 8: Effects of CD4+ T cells on CD8+ T cells.

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Data availability

Raw data are publicly available, and GEO links are provided. The RNA-seq datasets have been deposited in the NCBI GEO database under primary accession number GSE235665. For the transcriptomic analysis, reads were mapped to mm10 (v3.0.0) for mouse data and to hg19 (v3.0.0) for human data. Source data are provided with this paper.

Code availability

All codes for bioinformatic analysis were deposited in our GitHub repository (https://github.com/vijaybioinfo/UC_2024).

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Acknowledgements

We recognize La Jolla Institute Flow Core Facility for their assistance with cell sorting on a FACSAria Fusion Cell Sorter (supported by NIH grant S10 RR027366); K. Dobaczewska, S. McArdle (supported by Chan Zuckerberg Initiative and Silicon Valley Community Foundation) and Z. Mikulski for assistance with microscopy on a Zeiss LSM 880 confocal laser scanning microscope (supported by NIH grant S10OD021831); K. Kim for assistance with colon histology assessment; and H. Simon for assistance with library preparation and next-generation sequencing using Illumina NovaSeq 6000 (supported by NIH grant S10 OD025052). Supported by the De Laszlo Foundation (R.H.) and the William K. Bowes Jr Foundation, Kyowa Kirin, Inc. (KKNA). (P.V.), NIH grant DK46763 (M.K.) and NIH grant F32 AI 140581 (D.G.). The funders have no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Authors and Affiliations

Authors

Contributions

M.K., P.V., F.C. and T.S.-E. conceived of the work; Y.L. performed and analyzed experiments in mouse model of colitis under the supervision of M.K.; R.H. coordinated clinical assessments, patient recruitment, and collection and processing of colonic samples under the supervision of F.C. and T.S.-E.; A.D. and C.M. coordinated clinical assessments, patient recruitment, and collection and processing of colonic tissue samples for patients with UC and controls under the supervision of T.P.-J.; C.R.-S. and F.E.C.-C. performed bioinformatic analysis under the supervision of G.S. and P.V.; D.A.G., J.C. and R.H. performed sample processing and sorting of T cells from human samples for single-cell transcriptomic analysis; G.A. analyzed immunofluorescence staining under the supervision of M.K.; Y.L. analyzed data under the supervision of M.K. and P.V.; Y.L. wrote the first draft of the paper that was revised by M.K. and P.V.

Corresponding authors

Correspondence to Mitchell Kronenberg or Pandurangan Vijayanand.

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Competing interests

P.V. has consulted for Merck and Co., and M.K. has served on the scientific advisory board of Prometheus Biosciences. The other authors declare no competing interests.

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Nature Immunology thanks Vassiliki Boussiotis and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: L. A. Dempsey, in collaboration with the Nature Immunology team. Peer reviewer reports are available.

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Extended data

Extended Data Fig. 1 Stem-like T cells are present in colonic tissue.

a, Flow-cytometric plots show sequential gating strategy used for isolating T cells from colonic tissue samples for single-cell RNA-seq, CITE-seq and TCR-seq analyses. b, Violin plots show the per-cell distribution of unique genes, unique molecular identifiers (UMI), and percentage of UMI mapped to mitochondrial genome in T cell clusters in colonic tissue samples (n = 36). Box plots extend from the 25th to 75th percentile and the center line represents the median. Whiskers are bounded by 25th percentile - 1.5*interquartile range or 75th percentile + 1.5*interquartile range. c, UMAP showing Seurat-based clustering of 13,887 T cells (7,047 CD8+, 6,743 CD4+ and 97 cycling T cells), colored based on cluster type; labels on clusters indicate T cell subsets and their assigned cluster identity. d, UMAP illustrating log normalized UMI counts of CD4 and CD8α surface antibody in single cells, measured by CITE-seq (top), and Seurat-normalized expression levels of CD4 and CD8A transcripts in single cells (bottom). e, GSEA plot shows enrichment of indicated gene signatures in the indicated cell clusters compared to the rest of the CD4+ and CD8+ T cells; q value (FDR) and normalized enrichment score (NES) determined using fgsea package on R.

Extended Data Fig. 2 Analysis of published single-cell transcriptomic studies in UC cohorts.

a, Analysis of published single-cell datasets from UC cohorts4,5,6. UMAP showing Seurat-based clustering of colonic T cells, colored based on cluster type; the major T cell subsets (annotated by authors) present in each cluster are shown in Supplementary Table 5. UMAPs (left to right) show Seurat-normalized expression levels of genes enriched in the stem-like CD4+ T cells, stem-like CD8+ T cells, and CXCL13 or CXCR5 gene transcripts in single cells. Stem-like genes were identified in our dataset (Supplementary Table 4).

Extended Data Fig. 3 Stem-like T cells are enriched in inflamed regions.

a, Percentage of the CD4+ and CD8+ colonic T cell subsets from the indicated sources of colonic tissue samples obtained from each study subject. b, Plot shows Z-score average expression (color scale) and percentage of cells (size scale) that expressed the selected gene transcripts that were significantly enriched (FDR ≤ 0.05) in the indicated colonic CD8+ T cell clusters when compared to the other CD8+ T cells. c, UMAP shows Seurat-normalized expression levels of the indicated gene transcripts in single colonic CD8+ colonic T cells.

Extended Data Fig. 4 Expression of TFH and pro-inflammatory genes by colonic T cells in UC.

a, (Left) CD4, CD8, BCL-6 immunohistochemistry staining of colonic tissue samples. Indicated markers are light red, the CD31 marker staining, as described in methods, is in a dark brown color. (Right) BCL-6+CD4+ and BCL-6+CD8+ T cells counts from the indicated groups (n = 5 for healthy; n = 4 for inflamed tissue from patients with active UC). b, UMAPs show Seurat-normalized expression level of indicated gene transcripts in colonic CD4+ single cells. c, UMAP shows Seurat-normalized expression level of IL21R transcripts in colonic single CD4+ and CD8+ cells. Bar graphs in (a) depict mean ± SEM, each symbol represents data from an individual human subject. Statistical significance for the comparisons was computed using Student’s unpaired two-tailed t test (a).

Source data

Extended Data Fig. 5 BCL-6-deficient mouse CD4+ T cells induced less colitis and had reduced TH17 cells.

a, Flow-cytometric plots show sequential gating strategy for isolating CD4+CD45RBhighCD25 T cells from spleen. b, Three experimental repeats of adoptive T cell transfer model of colitis in which 2.5 ×105 splenic CD4+CD45RBhighCD25 T cells from Bcl6fl/flCd4Cre mice or Bcl6fl/fl mice were transferred into Rag1/ mice (numbers of mice in each experiment are shown in the figure); Body weight measurements of recipient Rag1/ mice; plots depicts mean ± SEM. c, Flow-cytometric plots show sequential gating strategy for isolating CD4+ T cells from colon LP of recipient Rag1/ mice and analyzing cells for intracellular cytokine production. d, Representative flow cytometry contour plots and frequency of colon LP CD4+ T cells that express the indicated cytokines following ex vivo stimulation with PMA plus ionomycin for 4 hours (Bcl6fl/fl n = 4; Bcl6fl/flCd4Cre n = 5). e, UMAPs show Seurat-normalized expression levels of Ccl5 and Gzmk gene transcripts in single colonic CD4+ T cells. f, Representative flow cytometry contour plots and frequency of CD4+ T cells that express IL-17A after in vitro differentiation under TH17 conditions (Bcl6fl/fl n = 3; Bcl6fl/flCd4Cre n = 3); experiment was performed once. Bar graphs in (d, f) depict mean ± SEM, each symbol represents data from an individual mouse; all data from are representative from one of at least two independent experiments with similar results. Statistical significance for the comparisons was computed using two-way ANOVA (b), Student’s unpaired two-tailed t test (d, f).

Source data

Extended Data Fig. 6 TCF1-deficiency attenuated pathogenicity of CD4+ T cells.

a, (Left) CD4, CD8, TCF1, and Hoechst immunofluorescence staining of colonic tissues. TCF1 detects proliferating epithelial cells as well as some T cells. Nuclear TCF1 staining in T cells is surrounded by a rim of CD4 or CD8 staining, as indicated by arrows for representative cells. (Right) TCF1+CD4+ and TCF1+CD8+ T cell counts from the indicated groups (n = 7 for healthy; n = 11 for inflamed tissue from patients with active UC). b, CD4+ T cell numbers from colon LP of the indicated recipient Rag1/ mice (Tcf7fl/fl n = 6; Tcf7fl/flCd4Cre n = 6). c, Frequency of unstimulated colon LP CD4+ T cells that expressed surface CD8a or FOXP3+ and colon CD4+ T cells that expressed IFNg or IL-17A following ex vivo stimulation with PMA plus ionomycin for 4 hours (Tcf7fl/fl n = 7; Tcf7fl/flCd4Cre n = 6). d, Body weight measurements of recipient Rag1/ mice (Tcf7fl/fl n = 6; Tcf7fl/flCd4Cre n = 6); the graph depicts mean ± SEM. Bar graphs in (a) depict mean ± SEM, each symbol represents data from an individual human subject. Bar graphs in (b-c) depict mean ± SEM, each symbol represents data from an individual mouse. Data (b-c) are representative from one of at least two independent experiments with similar results. Statistical significance for the comparisons was computed using Mann-Whitney two-sided test (a), Student’s unpaired two-tailed t test (b,c), two-way ANOVA (d).

Source data

Extended Data Fig. 7 TCF1 expressing stem-like mouse CD4+ T cells induced more colitis.

a, Flow-cytometric plots showing co-staining of intracellular GFP and TCF1 in the indicated mice. b, Flow-cytometric plots showing the frequency of GFP+CD4+ and GFP+CD8+ T cells in the spleen of Tcf7GFP reporter mice. c, GSEA plot shows enrichment of the indicated gene signatures in the GFP+CD4+ and GFPCD4+ T cells in colon LP lymphocytes (LPL) of recipient Rag1/ mice. d, Body weight measurements of the secondary recipient Rag1/ mice (n = 4 or 6 for each group); the graph depicts mean ± SEM. e, Representative histology images in Fig. 7d. f, CD4+ T cell numbers from colon LP of the indicated recipient Rag1/ mice (n = 4 or 6 for each group). Bar graphs in (f) depict mean ± SEM, each symbol represents data from an individual mouse. Data (d,e,f) are from one experiment. Statistical significance for the comparisons was computed using two-way ANOVA (d), Kruskal–Wallis test and adjustments were made for multiple comparisons (f).

Source data

Extended Data Fig. 8 Mouse colonic CD8+ T function was dependent of CD4+ T cells.

a, Flow-cytometric plots show sequential gating strategy used for isolating TCRβ+CD8β+CD4 T cells from spleen. b, Histology scores for the degree of colon tissue inflammation (n = 5 for CD4+ + CD8+ T cell transfer; n = 6 for CD8+ T cell transfer). c, Representative flow cytometry contour plots and frequency of colon LP CD8+ T cells that expressed the indicated cytokines following ex vivo stimulation with PMA-Ionomycin for 4 hours (n = 5 for CD4+ + CD8+ T cell transfer; n = 6 for CD8+ T cell transfer). Bar graphs in (b,c) depict mean ± SEM, each symbol represents data from an individual mouse; all data from are representative of one of two independent experiments with similar results except that histology in (b) was performed only once. Statistical significance for the comparisons was computed using one-way ANOVA (b), Student’s unpaired two-tailed t test (c).

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Supplementary information

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Li, Y., Ramírez-Suástegui, C., Harris, R. et al. Stem-like T cells are associated with the pathogenesis of ulcerative colitis in humans. Nat Immunol 25, 1231–1244 (2024). https://doi.org/10.1038/s41590-024-01860-7

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