Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The transcription factor Aiolos restrains the activation of intestinal intraepithelial lymphocytes

Nature Immunology volume 25, pages 77–87 (2024)Cite this article

Subjects

Abstract

Intestinal intraepithelial lymphocytes (IELs) exhibit prompt innate-like responses to microenvironmental cues and require strict control of effector functions. Here we showed that Aiolos, an Ikaros zinc-finger family member encoded by Ikzf3, acted as a regulator of IEL activation. Ikzf3−/− CD8αα+ IELs had elevated expression of NK receptors, cytotoxic enzymes, cytokines and chemokines. Single-cell RNA sequencing of Ikzf3−/− and Ikzf3+/+ IELs showed an amplified effector machinery in Ikzf3−/− CD8αα+ IELs compared to Ikzf3+/+ counterparts. Ikzf3−/− CD8αα+ IELs had increased responsiveness to interleukin-15, which explained a substantial part, but not all, of the observed phenotypes. Aiolos binding sites were close to those for the transcription factors STAT5 and RUNX, which promote interleukin-15 signaling and cytolytic programs, and Ikzf3 deficiency partially increased chromatin accessibility and histone acetylation in these regions. Ikzf3 deficiency in mice enhanced susceptibility to colitis, underscoring the relevance of Aiolos in regulating the effector function in IELs.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: uIELs express Aiolos and Aiolos controls their activation.
Fig. 2: Aiolos restrains the activation of uIELs in a cell-intrinsic manner.
Fig. 3: Aiolos impacts the Tcf7-Il2rbhi subset of CD8αα+ IELs.
Fig. 4: Aiolos-deficient IELs are hyperresponsive to IL-15.
Fig. 5: Inflammatory conditions control Aiolos expression.
Fig. 6: Aiolos binds in close proximity of IEL effector genes and STAT5 binding regions.
Fig. 7: Aiolos shapes distinct epigenetic landscapes in uIELs.

Similar content being viewed by others

Data availability

Sequencing data of RNA-seq, ATAC-seq, scRNA-seq, microarray and CUT&RUN-seq are deposited in the Gene Expression Omnibus (GSE220030). For STAT5, RUNX1 and RUNX3 binding analysis, published ChIP–seq data were used (GSE100674, GSE93755, GSE50131).

Code availability

Codes will be provided upon reasonable request. Please contact M. Colonna for further information.

References

  1. Mayassi, T. & Jabri, B. Human intraepithelial lymphocytes. Mucosal Immunol. 11, 1281–1289 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Olivares-Villagomez, D. & Van Kaer, L. Intestinal intraepithelial lymphocytes: sentinels of the mucosal barrier. Trends Immunol. 39, 264–275 (2018).

    CAS  PubMed  Google Scholar 

  3. Colonna, M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. Immunity 48, 1104–1117 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Cheroutre, H., Lambolez, F. & Mucida, D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol. 11, 445–456 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. McDonald, B. D., Jabri, B. & Bendelac, A. Diverse developmental pathways of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol. 18, 514–525 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. McFarland, A. P. et al. Multi-tissue single-cell analysis deconstructs the complex programs of mouse natural killer and type 1 innate lymphoid cells in tissues and circulation. Immunity 54, 1320–1337 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Van Acker, A. et al. A murine intestinal intraepithelial NKp46-negative innate lymphoid cell population characterized by group 1 properties. Cell Rep. 19, 1431–1443 (2017).

    PubMed  Google Scholar 

  8. Mayassi, T., Barreiro, L. B., Rossjohn, J. & Jabri, B. A multilayered immune system through the lens of unconventional T cells. Nature 595, 501–510 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Hayday, A., Theodoridis, E., Ramsburg, E. & Shires, J. Intraepithelial lymphocytes: exploring the Third Way in immunology. Nat. Immunol. 2, 997–1003 (2001).

    CAS  PubMed  Google Scholar 

  10. Abadie, V., Discepolo, V. & Jabri, B. Intraepithelial lymphocytes in celiac disease immunopathology. Semin. Immunopathol. 34, 551–566 (2012).

    CAS  PubMed  Google Scholar 

  11. Catalan-Serra, I., Sandvik, A. K., Bruland, T. & Andreu-Ballester, J. C. Gammadelta T cells in Crohn’s disease: a new player in the disease pathogenesis? J. Crohns Colitis 11, 1135–1145 (2017).

    PubMed  Google Scholar 

  12. Atlasy, N. et al. Single cell transcriptomic analysis of the immune cell compartment in the human small intestine and in Celiac disease. Nat. Commun. 13, 4920 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Heizmann, B., Kastner, P. & Chan, S. The Ikaros family in lymphocyte development. Curr. Opin. Immunol. 51, 14–23 (2018).

    CAS  PubMed  Google Scholar 

  14. Koipally, J., Renold, A., Kim, J. & Georgopoulos, K. Repression by Ikaros and Aiolos is mediated through histone deacetylase complexes. EMBO J. 18, 3090–3100 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhang, J. et al. Harnessing of the nucleosome-remodeling-deacetylase complex controls lymphocyte development and prevents leukemogenesis. Nat. Immunol. 13, 86–94 (2011).

    PubMed  PubMed Central  Google Scholar 

  16. Molnar, A. & Georgopoulos, K. The Ikaros gene encodes a family of functionally diverse zinc finger DNA-binding proteins. Mol. Cell Biol. 14, 8292–8303 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Georgopoulos, K. et al. The Ikaros gene is required for the development of all lymphoid lineages. Cell 79, 143–156 (1994).

    CAS  PubMed  Google Scholar 

  18. Quintana, F. J. et al. Aiolos promotes TH17 differentiation by directly silencing Il2 expression. Nat. Immunol. 13, 770–777 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Morgan, B. et al. Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation. EMBO J. 16, 2004–2013 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang, J. H. et al. Aiolos regulates B cell activation and maturation to effector state. Immunity 9, 543–553 (1998).

    CAS  PubMed  Google Scholar 

  21. Qiu, J. et al. Tissue signals imprint Aiolos expression in ILC2s to modulate type 2 immunity. Mucosal Immunol. 14, 1306–1322 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Felton, J. M. et al. Aiolos regulates eosinophil migration into tissues. Mucosal Immunol. 14, 1271–1281 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Holmes, M. L. et al. Peripheral natural killer cell maturation depends on the transcription factor Aiolos. EMBO J. 33, 2721–2734 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Cella, M. et al. Subsets of ILC3-ILC1-like cells generate a diversity spectrum of innate lymphoid cells in human mucosal tissues. Nat. Immunol. 20, 980–991 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Mazzurana, L. et al. Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3-ILC1/NK cell transdifferentiation. Eur. J. Immunol. 49, 1344–1355 (2019).

    CAS  PubMed  Google Scholar 

  26. Whang, M. I., Guerra, N. & Raulet, D. H. Costimulation of dendritic epidermal gammadelta T cells by a new NKG2D ligand expressed specifically in the skin. J. Immunol. 182, 4557–4564 (2009).

    CAS  PubMed  Google Scholar 

  27. Puddington, L., Olson, S. & Lefrancois, L. Interactions between stem cell factor and c-Kit are required for intestinal immune system homeostasis. Immunity 1, 733–739 (1994).

    CAS  PubMed  Google Scholar 

  28. Shui, J. W. et al. HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria. Nature 488, 222–225 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Rezende, R. M. et al. gammadelta T cell-secreted XCL1 mediates anti-CD3-induced oral tolerance. J. Immunol. 203, 2621–2629 (2019).

    PubMed  Google Scholar 

  30. Zehn, D. et al. ‘Stem-like’ precursors are the fount to sustain persistent CD8+ T cell responses. Nat. Immunol. 23, 836–847 (2022).

  31. Wu, J. et al. An activating immunoreceptor complex formed by NKG2D and DAP10. Science 285, 730–732 (1999).

    CAS  PubMed  Google Scholar 

  32. Lanier, L. L. DAP10- and DAP12-associated receptors in innate immunity. Immunol. Rev. 227, 150–160 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Nixon, B. G. et al. Cytotoxic granzyme C-expressing ILC1s contribute to antitumor immunity and neonatal autoimmunity. Sci. Immunol. 7, eabi8642 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Yomogida, K. et al. Hobit confers tissue-dependent programs to type 1 innate lymphoid cells. Proc. Natl Acad. Sci. USA 118, e2117965118 (2021).

  35. Friedrich, C. et al. Effector differentiation downstream of lineage commitment in ILC1s is driven by Hobit across tissues. Nat. Immunol. 22, 1256–1267 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Gilfillan, S. et al. NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation. Nat. Immunol. 3, 1150–1155 (2002).

  37. Ma, L. J., Acero, L. F., Zal, T. & Schluns, K. S. Trans-presentation of IL-15 by intestinal epithelial cells drives development of CD8alphaalpha IELs. J. Immunol. 183, 1044–1054 (2009).

    CAS  PubMed  Google Scholar 

  38. Zhou, R., Wei, H., Sun, R. & Tian, Z. Recognition of double-stranded RNA by TLR3 induces severe small intestinal injury in mice. J. Immunol. 178, 4548–4556 (2007).

    CAS  PubMed  Google Scholar 

  39. Lodolce, J. P. et al. T cell-independent interleukin 15rα signals are required for bystander proliferation. J. Exp. Med. 194, 1187–1194 (2001).

  40. Zhou, R. et al. NKG2D recognition mediates Toll-like receptor 3 signaling-induced breakdown of epithelial homeostasis in the small intestines of mice. Proc. Natl Acad. Sci. USA 104, 7512–7515 (2007).

  41. Longhi, M. P. et al. Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant. J. Exp. Med 206, 1589–1602 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Chassaing, B., Aitken, J. D., Malleshappa, M. & Vijay-Kumar, M. Dextran sulfate sodium (DSS)-induced colitis in mice. Curr. Protoc. Immunol. 104, 152511–152514 (2014).

    Google Scholar 

  43. Maekawa, Y. et al. Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity. Nat. Immunol. 9, 1140–1147 (2008).

    CAS  PubMed  Google Scholar 

  44. Hahm, K. et al. Helios, a T cell-restricted Ikaros family member that quantitatively associates with Ikaros at centromeric heterochromatin. Genes Dev. 12, 782–796 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Schjerven, H. et al. Selective regulation of lymphopoiesis and leukemogenesis by individual zinc fingers of Ikaros. Nat. Immunol. 14, 1073–1083 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Hollenhorst, P. C., Shah, A. A., Hopkins, C. & Graves, B. J. Genome-wide analyses reveal properties of redundant and specific promoter occupancy within the ETS gene family. Genes Dev. 21, 1882–1894 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Ma, S. et al. Ikaros and Aiolos inhibit pre-B-cell proliferation by directly suppressing c-Myc expression. Mol. Cell Biol. 30, 4149–4158 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Bjorklund, C. C. et al. Rate of CRL4(CRBN) substrate Ikaros and Aiolos degradation underlies differential activity of lenalidomide and pomalidomide in multiple myeloma cells by regulation of c-Myc and IRF4. Blood Cancer J. 5, e354 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Peloquin, J. M. et al. Characterization of candidate genes in inflammatory bowel disease-associated risk loci. JCI Insight 1, e87899 (2016).

    PubMed  PubMed Central  Google Scholar 

  50. Katerndahl, C. D. S. et al. Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival. Nat. Immunol. 18, 694–704 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Heizmann, B. et al. Ikaros antagonizes DNA binding by STAT5 in pre-B cells. PLoS ONE 15, e0242211 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Read, K. A. et al. Aiolos represses CD4+ T cell cytotoxic programming via reciprocal regulation of TFH transcription factors and IL-2 sensitivity. Nat. Commun. 14, 1652 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Abadie, V. et al. IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease. Nature 578, 600–604 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Lefrancois, L. & Lycke, N. Isolation of mouse small intestinal intraepithelial lymphocytes, Peyer’s patch, and lamina propria cells. Curr. Protoc. Immunol. 3, 19 (2001).

  55. Buenrostro, J. D. et al. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat. Methods 10, 1213–1218 (2013).

Download references

Acknowledgements

We thank the Genome Technology Access Center at the McDonnell Genome Institute at Washington University for RNA-seq, ATAC-seq, CUT&RUN-seq and scRNA-seq. The center is supported in part by the Alvin J. Siteman Cancer Center and Barnes-Jewish Hospital, and the Institute of Clinical and Translational Sciences (ICTS). The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant (P30 CA091842) and the ICTS is funded by the National Institutes of Health’s NCATS Clinical and Translational Science Award (CTSA) program grant (UL1 TR002345). We thank E. Lantelme and D. Brinja and the Pathology and Immunology Flow Cytometry Core for cell sorting. This work was supported by grants UO1 AI095542, RO1 DK126969, RO1 DK132327, RO1 AI134035, RO1 DK124699 and U19 AI142733 (to M. Colonna). K.Y. was supported by the Rheumatology Research Foundation Tobé and Stephen E. Malawista, MD Endowment in Academic Rheumatology, CHRC K12 and K08DK128544.

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of Colorado Anschutz Medical Campus, Denver, CO, USA

    Kentaro Yomogida

  2. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

    Kentaro Yomogida, Tihana Trsan, Raki Sudan, Patrick F. Rodrigues, Alina Ulezko Antonova, Marina Cella, Susan Gilfillan & Marco Colonna

  3. Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO, USA

    Harshad Ingle & Megan T. Baldridge

  4. Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA

    Blanda Di Luccia

  5. Department of Microbial Infection and Immunity, Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, USA

    Patrick L. Collins & Eugene M. Oltz

Authors
  1. Kentaro Yomogida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tihana Trsan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Raki Sudan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Patrick F. Rodrigues
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alina Ulezko Antonova
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Harshad Ingle
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Blanda Di Luccia
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Patrick L. Collins
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marina Cella
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Susan Gilfillan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Megan T. Baldridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Eugene M. Oltz
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Marco Colonna
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.Y., T.T., R.S., P.F.R., A.U.A., H.I., B.D. and P.L.C. performed experiments and analyzed the data. K.Y., H.I., P.L.C., M. Cella, E.M.O., M.T.B. and M. Colonna designed experiments. H.I. and M.T.B. provided crucial reagents. S.G. maintained the mouse colony. K.Y. and M. Colonna wrote the paper with input from all authors.

Corresponding author

Correspondence to Marco Colonna.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Immunology thanks Bana Jabri and Pandurangan Vijayanand for their contribution to the peer review of this work. Primary Handling Editor: Ioana Visan, in collaboration with the Nature Immunology team.

Additional information

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

Extended data

Extended Data Fig. 1 Aiolos does not alter abundance of IELs.

Cell counts of γδ IEL, DN IEL, DP IEL, CD4+ IEL and CD8αβ+ IEL from small intestine in Ikzf3+/+ and Ikzf3−/− mice. Data are representative of two independent experiments (n = 4) and all samples are biological replicates. DN = double negative, DP = double positive (CD4 cytotoxic), Data represent mean ± SD. P values were determined by two-tailed, unpaired Student’s t-test.

Extended Data Fig. 2 NKG2D does not directly induce cytotoxicity in unconventional IELs.

a, Gene expression of NK receptors associated with DAP12 (Klrk1, Klrc2 and Klra8) in γδ IEL and DN IEL from small intestine in Ikzf3+/+ and Ikzf3−/− mice based on RNA-seq. b, γδ IEL and DN IEL from small intestine in Ikzf3+/+ and Ikzf3−/− mice were sorted, and co-cultured with RMA-S or RMA-S overexpressing Rae1γ. Frequency of live target cells are shown. Data showed one experiment in b and all samples are biological replicates. P values in a were calculated by Wald test (DEseq2). WT=Ikzf3 +/+ ; KO=Ikzf3 –/–.

Extended Data Fig. 3 scRNA-seq demonstrate heterogeneity of IELs.

a, UMAP plots of 25,966 cells of Ikzf3+/+ small intestine CD45+ IELs. b, Representative UMAP plots depicting expression of Trac, Cd8a, Tcrg-V7 and Tcrg-V1. c, Heatmap displaying top differentially expressed genes in clusters designated as CD8aa-1, CD8αα-2, CD8αα-3, CD8αα-4, CD8αα-5, CD8αα-6, CD8αβ+, CD4+, pDC, B cells and plasma cells.

Extended Data Fig. 4 CD8αα+ IELs comprise diverse groups of cells.

a, Heatmap displaying top differentially expressed genes in clusters designated as Ikzf3−/−Tcf7−Il2rbhi, Ikzf3+/+Tcf7−Il2rbhi, Tcf7−Il2rblo, Tcf7+, stressed CD8αα, lipidolytic CD8αα, proliferating CD8αα and IFN-stimulated CD8αα. b, Representative UMAP plots depicting expression of Klra4, Klra8, Klrc2, Il2ra, Cd200r1 Cd200r2, Lat, Lat2, Lag3, Cd200r4, Pdcd1, Havcr2, Lair2 and Il7r.

Extended Data Fig. 5 Ikzf3-deficiency enhances responses to IL-15.

a, Heatmap showing differentially expressed cytokine genes in the duodenum and ileum from Ikzf3+/+ mice. b-d, Flow cytometry plots and quantification of NKG2A (b), Ly49A and D (c) and NKG2D (d) on γδ IEL and DN IEL from small intestine in Ikzf3+/+ and Ikzf3−/− mice 72 hours after culturing with either 10 ng/ml or 100 ng/ml of IL-15. Data are representative of two independent experiments and all samples are biological replicates. n=8 in b, c and n=5 (Ikzf3+/+) and 6 (Ikzf3−/−) in d. Data represent mean ± SD. P values were calculated by two-way ANOVA with Tukey’s multiple comparisons test in b, c and d.

Extended Data Fig. 6 Generation and phenotype of Aiolos conditional deficient mice.

a, Diagram of the construct for conditional Ikzf3fl/fl mice showing LoxP sites flanking exon 4 and exon 6. b, Representative histograms show tdTomato expression in γδ IEL and DN IEL, DP IEL, CD4+ IEL, CD8αβ+ IEL, NK cells and B cells from small intestine in E8ICre R26RtdTomato mice. c, Representative image of colon from Ikzf3fl/fl and E8ICreIkzf3fl/fl mice at day 4 post DSS administration in the drinking water. Data are representative of two independent experiments.

Extended Data Fig. 7 Interactions of Aiolos with STAT5 and RUNX members.

a, A pie chart showing the chromosomal location of Aiolos binding regions in the indicated cell types. b, A Venn diagram depicting Aiolos binding peaks in γδ IELs and DN IELs. c, Represenative histogram plots and quantification of pSTAT5 expression in γδ IEL, DN IEL from the small intestine of Ikzf3+/+ and Ikzf3−/− mice. Cells were either not stimulated or stimulated for 15 minutes with IL-15 (100 ng/ml). d, The results of permutation test designed to analyze the significance of overlap of Aiolos with either STAT5, RUNX1 or RUNX3. Evperm: the number of permutation events, Evobs: the number of observed events (overlapped peak counts). Data are representative of two independent experiments and all samples are biological replicates (n = 4 in c). P values were calculated by unpaired, two-tailed Student’s t-test in c and Permutation test in d (ChIPpeakAnno). Data represent mean ± SD. pSTAT5 = phosphorylated STAT5, UTR = untranslated region.

Extended Data Fig. 8 Aiolos shapes a distinct epigenetic landscape.

a, Gene expression of IKZF family members in γδ IEL and DN IEL from the small intestine in Ikzf3+/+ and Ikzf3−/− mice based on RNAseq (see Fig. 2). The expression of Ikzf3 in Ikzf3–/– IEL reflects a portion of the nonfuntional transcript present in the knockout mouse. b, Venn diagrams depicting overlap of Aiolos binding regions, differential H3K27ac peaks and DAR, and the result of permutation test designed to analyze the significance of overlap of differential H3K27ac peaks with DAR in γδ IELs and DN IELs. FDR were calculated by Wald test (DESeq2) in a and P values were calculated Permutation test in b (ChIPpeakAnno). DAR = differential accessible regions.

Supplementary information

Reporting Summary

Supplementary Tables 1 and 2

Supplementary Table 1 Comprehensive list of DEGs in the indicated cell types, along with their respective associations with DAR, differential H3K27ac, binding of Aiolos, STAT5, RUN1 or RUNX3. ‘+’ indicates positive association, whereas ‘–’ denotes no association. Supplementary Table 2 Quality-control metrics of ATAC-seq and CUT&RUN-seq for Aiolos and H3K27ac.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yomogida, K., Trsan, T., Sudan, R. et al. The transcription factor Aiolos restrains the activation of intestinal intraepithelial lymphocytes. Nat Immunol 25, 77–87 (2024). https://doi.org/10.1038/s41590-023-01693-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41590-023-01693-w

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing