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Dynamic transcriptional activity and chromatin remodeling of regulatory T cells after varied duration of interleukin-2 receptor signaling

Nature Immunology volume 23, pages 802–813 (2022)Cite this article

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Abstract

Regulatory T (Treg) cells require (interleukin-2) IL-2 for their homeostasis by affecting their proliferation, survival and activation. Here we investigated transcriptional and epigenetic changes after acute, periodic and persistent IL-2 receptor (IL-2R) signaling in mouse peripheral Treg cells in vivo using IL-2 or the long-acting IL-2-based biologic mouse IL-2–CD25. We show that initially IL-2R-dependent STAT5 transcription factor-dependent pathways enhanced gene activation, chromatin accessibility and metabolic reprogramming to support Treg cell proliferation. Unexpectedly, at peak proliferation, less accessible chromatin prevailed and was associated with Treg cell contraction. Restimulation of IL-2R signaling after contraction activated signature IL-2-dependent genes and others associated with effector Treg cells, whereas genes associated with signal transduction were downregulated to somewhat temper expansion. Thus, IL-2R-dependent Treg cell homeostasis depends in part on a shift from more accessible chromatin and expansion to less accessible chromatin and contraction. Mouse IL-2–CD25 supported greater expansion and a more extensive transcriptional state than IL-2 in Treg cells, consistent with greater efficacy to control autoimmunity.

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Fig. 1: Sustained IL-2R signaling and extensive gene activation drives Treg cell expansion in vivo.
Fig. 2: Regulatory transcriptional changes in response to persistent IL-2R signaling support Treg cell expansion.
Fig. 3: Sustained IL-2R signaling reprograms Treg cell energetic metabolism.
Fig. 4: Repeated administration of high doses of mIL-2 does not fully recapitulate the response of Treg cells to mIL-2–CD25.
Fig. 5: Chromatin accessibility in Treg cells is dynamically regulated by mIL-2–CD25.
Fig. 6: ATAC–seq/RNA-seq integration uncovers new mediators induced by a persistent IL-2R signaling leading to Treg cell expansion.
Fig. 7: mIL-2–CD25-dependent increase in less accessible chromatin regions does not limit STAT5 activation or IL-2-dependent gene transcription after restimulation with mIL-2–CD25.

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Data availability

Data are deposited in the Gene Expression Omnibus under accession codes GSE163946 (RNA-seq) and GSE162030 (ATAC–seq). Source data are provided with this paper. Other data will be made available upon reasonable request.

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Acknowledgements

We thank A. S. Savio for technical assistance. J. Enten, P. Guevara, S. Saigh and N. Ward from the Flow Cytometry Core and M. Brooks, Y. Cardentey and J. Kemper from the Oncogenomics Core of the Sylvester Comprehensive Cancer Center (supported by National Institutes of Health (NIH) P30CA240139); and M. Struthers and F. Ramirez-Valle at Bristol Myers Squibb and A. Villarino at the University of Miami for critically reading the manuscript. This research was supported by funding to T.R.M. from Bristol Myers Squibb and the NIH (R01AI148675).

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Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Miami, Miami, FL, USA

    Alejandro Moro, Aixin Yu, Sunnie Hsiung & Thomas R. Malek

  2. Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA

    Zhen Gao, Lily Wang, Yuguang Ban, Aimin Yan, Corneliu M. Sologon & X. Steven Chen

  3. Division of Biostatistics, Department of Public Health Sciences, University of Miami, Miami, FL, USA

    Lily Wang, Yuguang Ban & X. Steven Chen

  4. John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA

    Lily Wang

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Contributions

Conception and design: A.M. and T.R.M. Acquisition of data: A.M., A. Yu, S.H. and C.M.S. Analysis and interpretation of data: A.M., Z.G., L.W., S.H., Y.B., A. Yan, X.S.C. and T.R.M. Manuscript writing: A.M. and T.R.M. All authors edited and approved the manuscript.

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Correspondence to Thomas R. Malek.

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Competing interests

The University of Miami and T.R.M. have patents pending on IL-2–CD25 fusion proteins (WO2016022671A1) and their use (PCT/US20/13152) that have been licensed exclusively to Bristol Myers Squibb, and this research has been supported in part by a collaboration and sponsored research and licensing agreement with Bristol Myers Squibb. The other authors declare no competing interests.

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Nature Immunology thanks Andrew Wells and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Jamie D. K. Wilson, in collaboration with the Nature Immunology team.

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Extended data

Extended Data Fig. 1 Sustained pSTAT5 activation of Treg by single injection of mIL-2/CD25 but not of mIL-2One sentence only.

Unfractionated splenocytes from mice (n = 3/group) were injected with mIL-2/CD25, mIL-2 or control PBS and stained with indicated antibodies. (a) Representative flow cytometry plots showing gating for Treg and (b) expression of pSTAT5+ of Tregs at each experimental condition.

Extended Data Fig. 2 Representative FACS gating strategy for sorted Treg at 72 hr post single injection of mIL-2/CD25.

CD4 + T cells from the spleen of CD4 + Foxp3 + -RFP + reporter mice were enriched with anti-CD4 magnetic beads and stained with FITC - anti-CD4 antibody. RFP + Treg were sorted as shown. Treg purity was typically greater than 98%.

Extended Data Fig. 3 Expression of DEGs (FDR < 0.01) at 4 hr after single injection of PBS, mIL2, or mIL2/CD25 using the same RNAseq data set as (Fig. 1d).

Heat map of K-means clustering of 789 differentially expressed genes in response to single injection or re-stimulation with mIL-2/CD25 versus control PBS. Clustering was done using Morpheus software (clustering type: K-means clustering, distance metric: 1-Pearson correlation). The colors in the map display the relative values within indicated experimental conditions. Blue indicates the lowest expression, white indicates intermediate expression, and red indicates the highest expression. Genes were grouped into three clusters on the basis of the expression similarity.

Extended Data Fig. 4 Significant upstream regulators (p value of overlap < 0.05; -2 ≤ z-score ≥ 2) at 1.5 hr post injection of mIL-2/CD25.

The horizontal bars denote the different regulators based on the activation z-score. Red color indicates activation, while blue color indicates inhibition. (b) Top gene network related to ‘Cellular Development, Cellular Growth and Proliferation, Lymphoid Tissue Structure and Development’ in Tregs 1.5 hrs post injection. TCR and STAT5 were identified as key hubs.

Extended Data Fig. 5 Significant modulated canonical pathways predicted by GSEA (a) or Ingenuity Pathway Analysis (IPA) (b) post single injection of mIL-2/CD25.

Cutoffs: GSEA FDR < 0.25; IPA p < 0.05; z-score of activation (orange: active ≥2; blue: inhibited ≤ -2). NES: normalized enrichment score.

Extended Data Fig. 6 Significant modulated upstream regulators predicted by IPA at each time post single administration of mIL-2/CD25.

p < 0.05; z-score of activation (orange: active ≥2; blue: inhibited ≤ -2).

Extended Data Fig. 7 (a) Western blot and (b) normalized (MYC/β-Actin) expression after densitometry analysis (n = 3) showing that MYC protein in Treg was significatively increased at 2 hr and persisted for up to 48 hr post single injection of mIL-2/CD25.

Protein extracts were obtained from FACS-sorted CD4 + Foxp3 + Tregs (>95% Foxp3 + ) isolated from C57BL/6J-Foxp3 + RFP mice at the indicated times after PBS, or mIL-2/CD25 (20 µg) injection. Expression levels of MYC and β-actin were analyzed by Western blotting with anti–MYC (10828-1-AP), or anti-β Actin (20536-1-AP) and revealed with a goat anti-rabbit polyclonal (G-21234). (b) One-way ANOVA with Tukey’s multiple comparisons test, ****p < 0.0001; ***p = 0.0002; n.s p = 0.1131. (c) RNA-seq time course expression of Myc or Slc7a5 in response to mIL-2/CD25. Data shown in (a) is from one representative gel where lanes were spliced to move relevant data neighboring to each other.

Source data

Extended Data Fig. 8 Sustained IL-2R signaling reprograms Treg energetic metabolism.

(a) Overlap between DEGs upregulated by mIL-2/CD25 at 72 hr post single injection (FDR < 0.01; fold change ≥ 1.5 X) and a set of mouse mitochondrial genes from the database Mitocarta 3.0. (b) Significant (upregulated, red; down-regulated, green) DEGs in the oxidative phosphorylation (OXPHOS) pathway in response to single injection of mIL-2/CD25 shown as components within each electron transport chain complex.

Extended Data Fig. 9 Enrichment analysis was performed on significantly over-represented genes and ten most significant groups are represented according to GO molecular function.

Reference dotted lines indicate p < 0.05 fold change cutoff.

Supplementary information

Reporting Summary

Supplementary Table 1

Significant differentially expressed genes from RNA-seq.

Supplementary Table 2

GSEA results.

Supplementary Table 3

Significant differentially accessible regions from ATAC–seq.

Supplementary Table 4

LOLA results.

Source data

Source Data Fig. 1

Statistical source data.

Source Data Fig. 3

Statistical source data.

Source Data Fig. 4

Statistical source data.

Source Data Fig. 5

Statistical source data.

Source Data Fig. 7

Statistical source data.

Source Data Extended Data Fig. 7

Unprocessed western blot.

Source Data Extended Data Fig. 7

Statistical source data.

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Moro, A., Gao, Z., Wang, L. et al. Dynamic transcriptional activity and chromatin remodeling of regulatory T cells after varied duration of interleukin-2 receptor signaling. Nat Immunol 23, 802–813 (2022). https://doi.org/10.1038/s41590-022-01179-1

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