Skip to main content
Log in

DNA demethylase Tet2 promotes the terminal maturation of natural killer cells

  • Original Article
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

The cytotoxicity feature to eliminate malignant cells makes natural killer (NK) cells a candidate for tumor immunotherapy. However, this scenario is currently hampered by inadequate understanding of the regulatory mechanisms of NK cell development. Ten-Eleven-Translocation 2 (Tet2) is a demethylase whose mutation was recently shown to cause phenotypic defects in NK cells. However, the role of Tet2 in the development and maturation of NK cells is not entirely clear. Here we studied the modulatory role of Tet2 in NK cell development and maturation by generating hematopoietic Tet2 knockout mice and mice with Tet2 conditional deletion in NKp46+ NK cells. The results showed that both hematopoietic and NK cell conditional deletion of Tet2 had no effect on the early steps of NK cell development, but impaired the terminal maturation of NK cells defined by CD11b, CD43, and KLRG1 expression. In the liver, Tet2 deletion not only prevented the terminal maturation of NK cells, but also increased the proportion of type 1 innate lymphoid cells (ILC1s) and reduced the proportion of conventional NK cells (cNK). Moreover, hematopoietic deletion of Tet2 lowered the protein levels of perforin in NK cells. Furthermore, hematopoietic deletion of Tet2 downregulated the protein levels of Eomesodermin (Eomes), but not T-bet, in NK cells. In conclusion, our results demonstrate that Tet2 plays an important role in the terminal maturation of NK cells, and the Eomes transcription factor may be involved.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article and the supplementary materials.

References

  1. Bjorkstrom NK, Ljunggren HG, Michaelsson J. Emerging insights into natural killer cells in human peripheral tissues. Nat Rev Immunol. 2016;16(5):310–20. https://doi.org/10.1038/nri.2016.34.

    Article  CAS  PubMed  Google Scholar 

  2. Lau CM, Wiedemann GM, Sun JC. Epigenetic regulation of natural killer cell memory. Immunol Rev. 2022;305(1):90–110. https://doi.org/10.1111/imr.13031.

    Article  CAS  PubMed  Google Scholar 

  3. Wolf NK, Kissiov DU, Raulet DH. Roles of natural killer cells in immunity to cancer, and applications to immunotherapy. Nat Rev Immunol. 2023;23(2):90–105. https://doi.org/10.1038/s41577-022-00732-1.

    Article  CAS  PubMed  Google Scholar 

  4. Crinier A, Narni-Mancinelli E, Ugolini S, Vivier E. SnapShot: natural killer cells. Cell. 2020;180(6):1280- e1. https://doi.org/10.1016/j.cell.2020.02.029.

    Article  CAS  Google Scholar 

  5. Wang W, Jiang J, Wu C. CAR-NK for tumor immunotherapy: clinical transformation and future prospects. Cancer Lett. 2020;472:175–80. https://doi.org/10.1016/j.canlet.2019.11.033.

    Article  CAS  PubMed  Google Scholar 

  6. Yilmaz A, Cui H, Caligiuri MA, Yu J. Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy. J Hematol Oncol. 2020;13(1):168. https://doi.org/10.1186/s13045-020-00998-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Abel AM, Yang C, Thakar MS, Malarkannan S. Natural killer cells: development, maturation, and clinical utilization. Front Immunol. 2018;9:1869. https://doi.org/10.3389/fimmu.2018.01869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Geiger TL, Sun JC. Development and maturation of natural killer cells. Curr Opin Immunol. 2016;39:82–9. https://doi.org/10.1016/j.coi.2016.01.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Male V, Nisoli I, Kostrzewski T, Allan DS, Carlyle JR, Lord GM, et al. The transcription factor E4bp4/Nfil3 controls commitment to the NK lineage and directly regulates Eomes and Id2 expression. J Exp Med. 2014;211(4):635–42. https://doi.org/10.1084/jem.20132398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Shehata HM, Hoebe K, Chougnet CA. The aged nonhematopoietic environment impairs natural killer cell maturation and function. Aging Cell. 2015;14(2):191–9. https://doi.org/10.1111/acel.12303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Huntington ND, Tabarias H, Fairfax K, Brady J, Hayakawa Y, Degli-Esposti MA, et al. NK cell maturation and peripheral homeostasis is associated with KLRG1 up-regulation. J Immunol. 2007;178(8):4764–70. https://doi.org/10.4049/jimmunol.178.8.4764.

    Article  CAS  PubMed  Google Scholar 

  12. Ito M, Maruyama T, Saito N, Koganei S, Yamamoto K, Matsumoto N. Killer cell lectin-like receptor G1 binds three members of the classical cadherin family to inhibit NK cell cytotoxicity. J Exp Med. 2006;203(2):289–95. https://doi.org/10.1084/jem.20051986.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Chiossone L, Chaix J, Fuseri N, Roth C, Vivier E, Walzer T. Maturation of mouse NK cells is a 4-stage developmental program. Blood. 2009;113(22):5488–96. https://doi.org/10.1182/blood-2008-10-187179.

    Article  CAS  PubMed  Google Scholar 

  14. Valero-Pacheco N, Beaulieu AM. Transcriptional regulation of mouse tissue-resident natural killer cell development. Front Immunol. 2020;11:309. https://doi.org/10.3389/fimmu.2020.00309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cortez VS, Ulland TK, Cervantes-Barragan L, Bando JK, Robinette ML, Wang Q, et al. SMAD4 impedes the conversion of NK cells into ILC1-like cells by curtailing non-canonical TGF-beta signaling. Nat Immunol. 2017;18(9):995–1003. https://doi.org/10.1038/ni.3809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Taggenbrock RLRE, van Gisbergen KPJM. ILC1: Development, maturation, and transcriptional regulation. Eur J Immunol. 2023;53(2):e2149435. https://doi.org/10.1002/eji.202149435.

    Article  CAS  PubMed  Google Scholar 

  17. Zhang J, Marotel M, Fauteux-Daniel S, Mathieu AL, Viel S, Marcais A, Walzer T. T-bet and Eomes govern differentiation and function of mouse and human NK cells and ILC1. Eur J Immunol. 2018;48(5):738–50. https://doi.org/10.1002/eji.201747299.

    Article  CAS  PubMed  Google Scholar 

  18. Gordon SM, Chaix J, Rupp LJ, Wu J, Madera S, Sun JC, et al. The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity. 2012;36(1):55–67. https://doi.org/10.1016/j.immuni.2011.11.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wagner JA, Wong P, Schappe T, Berrien-Elliott MM, Cubitt C, Jaeger N, et al. Stage-Specific requirement for Eomes in mature NK cell homeostasis and cytotoxicity. Cell Rep. 2020;31(9):107720. https://doi.org/10.1016/j.celrep.2020.107720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Deng Y, Kerdiles Y, Chu J, Yuan S, Wang Y, Chen X, et al. Transcription factor Foxo1 is a negative regulator of natural killer cell maturation and function. Immunity. 2015;42(3):457–70. https://doi.org/10.1016/j.immuni.2015.02.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cavalli G, Heard E. Advances in epigenetics link genetics to the environment and disease. Nature. 2019;571(7766):489–99. https://doi.org/10.1038/s41586-019-1411-0.

    Article  CAS  PubMed  Google Scholar 

  22. Yin J, Leavenworth JW, Li Y, Luo Q, Xie H, Liu X, et al. Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity. Proc Natl Acad Sci U S A. 2015;112(52):15988–93. https://doi.org/10.1073/pnas.1521740112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Degouve S, Tavares A, Viel S, Walzer T, Marcais A. NKp46-mediated Dicer1 inactivation results in defective NK-cell differentiation and effector functions in mice. Eur J Immunol. 2016;46(8):1902–11. https://doi.org/10.1002/eji.201546163.

    Article  CAS  PubMed  Google Scholar 

  24. Wu X, Zhang Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet. 2017;18(9):517–34. https://doi.org/10.1038/nrg.2017.33.

    Article  CAS  PubMed  Google Scholar 

  25. Cong B, Zhang Q, Cao X. The function and regulation of TET2 in innate immunity and inflammation. Protein Cell. 2021;12(3):165–73. https://doi.org/10.1007/s13238-020-00796-6.

    Article  CAS  PubMed  Google Scholar 

  26. Lio CJ, Rao A. TET enzymes and 5hmC in adaptive and innate immune systems. Front Immunol. 2019;10:210. https://doi.org/10.3389/fimmu.2019.00210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell. 2011;20(1):11–24. https://doi.org/10.1016/j.ccr.2011.06.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature. 2010;468(7325):839–43. https://doi.org/10.1038/nature09586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Boy M, Bisio V, Zhao LP, Guidez F, Schell B, Lereclus E, et al. Myelodysplastic syndrome associated TET2 mutations affect NK cell function and genome methylation. Nat Commun. 2023;14(1):588. https://doi.org/10.1038/s41467-023-36193-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Narni-Mancinelli E, Chaix J, Fenis A, Kerdiles YM, Yessaad N, Reynders A, et al. Fate mapping analysis of lymphoid cells expressing the NKp46 cell surface receptor. Proc Natl Acad Sci U S A. 2011;108(45):18324–9. https://doi.org/10.1073/pnas.1112064108.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kaasinen E, Kuismin O, Rajamaki K, Ristolainen H, Aavikko M, Kondelin J, et al. Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans. Nat Commun. 2019;10(1):1252. https://doi.org/10.1038/s41467-019-09198-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cenariu D, Iluta S, Zimta AA, Petrushev B, Qian L, Dirzu N, et al. Extramedullary hematopoiesis of the liver and spleen. J Clin Med. 2021;10(24):5831. https://doi.org/10.3390/jcm10245831.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gao YL, Souza-Fonseca-Guimaraes F, Bald T, Ng SS, Young A, Ngiow SF, et al. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Nat Immunol. 2017;18(9):1004–15. https://doi.org/10.1038/ni.3800.

    Article  CAS  PubMed  Google Scholar 

  34. Zhang C, Hu Y, Xiao W, Tian Z. Chimeric antigen receptor- and natural killer cell receptor-engineered innate killer cells in cancer immunotherapy. Cell Mol Immunol. 2021;18(9):2083–100. https://doi.org/10.1038/s41423-021-00732-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rawat P, Das A. Differential expression of disparate transcription factor regime holds the key for NK cell development and function modulation. Life Sci. 2022;297:120471. https://doi.org/10.1016/j.lfs.2022.120471.

    Article  CAS  PubMed  Google Scholar 

  36. Zhang J, Le Gras S, Pouxvielh K, Faure F, Fallone L, Kern N, et al. Sequential actions of EOMES and T-BET promote stepwise maturation of natural killer cells. Nat Commun. 2021;12(1):5446. https://doi.org/10.1038/s41467-021-25758-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ran GH, Lin YQ, Tian L, Zhang T, Yan DM, Yu JH, Deng YC. Natural killer cell homing and trafficking in tissues and tumors: from biology to application. Signal Transduct Target Ther. 2022;7(1):205. https://doi.org/10.1038/s41392-022-01058-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Huntington ND, Vosshenrich CA, Di Santo JP. Developmental pathways that generate natural-killer-cell diversity in mice and humans. Nat Rev Immunol. 2007;7(9):703–14. https://doi.org/10.1038/nri2154.

    Article  CAS  PubMed  Google Scholar 

  39. Berrien-Elliott MM, Sun Y, Neal C, Ireland A, Trissal MC, Sullivan RP, et al. MicroRNA-142 is critical for the homeostasis and function of type 1 innate lymphoid cells. Immunity. 2019;51(3):479–90 e6. https://doi.org/10.1016/j.immuni.2019.06.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pikovskaya O, Chaix J, Rothman NJ, Collins A, Chen YH, Scipioni AM, et al. Cutting edge: eomesodermin is sufficient to direct type 1 innate lymphocyte development into the conventional NK lineage. J Immunol. 2016;196(4):1449–54. https://doi.org/10.4049/jimmunol.1502396.

    Article  CAS  PubMed  Google Scholar 

  41. Peng V, Xing X, Bando JK, Trsan T, Di Luccia B, Collins PL, et al. Whole-genome profiling of DNA methylation and hydroxymethylation identifies distinct regulatory programs among innate lymphocytes. Nat Immunol. 2022;23(4):619–31. https://doi.org/10.1038/s41590-022-01164-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ivascu C, Wasserkort R, Lesche R, Dong J, Stein H, Thiel A, Eckhardt F. DNA methylation profiling of transcription factor genes in normal lymphocyte development and lymphomas. Int J Biochem Cell Biol. 2007;39(7-8):1523–38. https://doi.org/10.1016/j.biocel.2007.02.006.

    Article  CAS  PubMed  Google Scholar 

  43. Shen Q, Zhang Q, Shi Y, Shi Q, Jiang Y, Gu Y, et al. Tet2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation. Nature. 2018;554(7690):123–7. https://doi.org/10.1038/nature25434.

    Article  CAS  PubMed  Google Scholar 

  44. Li Z, Cai X, Cai CL, Wang J, Zhang W, Petersen BE, et al. Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood. 2011;118(17):4509–18. https://doi.org/10.1182/blood-2010-12-325241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. An J, Gonzalez-Avalos E, Chawla A, Jeong M, Lopez-Moyado IF, Li W, et al. Acute loss of TET function results in aggressive myeloid cancer in mice. Nat Commun. 2015;6:10071. https://doi.org/10.1038/ncomms10071.

    Article  CAS  PubMed  Google Scholar 

  46. Solary E, Bernard OA, Tefferi A, Fuks F, Vainchenker W. The Ten-Eleven Translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases. Leukemia. 2014;28(3):485–96. https://doi.org/10.1038/leu.2013.337.

    Article  CAS  PubMed  Google Scholar 

  47. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008;9(5):503–10. https://doi.org/10.1038/ni1582.

    Article  CAS  PubMed  Google Scholar 

  48. Goh W, Huntington ND. Regulation of murine natural killer cell development. Front Immunol. 2017;8:130. https://doi.org/10.3389/fimmu.2017.00130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Townsend MJ, Weinmann AS, Matsuda JL, Salomon R, Farnham PJ, Biron CA, et al. T-bet regulates the terminal maturation and homeostasis of NK and Valpha14i NKT cells. Immunity. 2004;20(4):477–94. https://doi.org/10.1016/s1074-7613(04)00076-7.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work is supported by the grant from the Chongqing Science and Technology Commission of China [cstc2021jcyj-jqX0006] and the National Natural Science Foundation of China [No. 81874313, 81922068, 81903627].

Author information

Authors and Affiliations

Authors

Contributions

This work was performed in collaboration with all the authors. YL, BY and HL are the first coauthors. YL designed and performed the experiments, analyzed the data, and wrote the manuscript. BY and HL performed the experiments, analyzed the data, and revised the manuscript. GR, LS, MM, XY, and QB performed the experiments. QB and DY designed the research, and revised and supervised the study. YD and YL devised the concept, designed the research, supervised the study, and wrote the manuscript.

Corresponding authors

Correspondence to Qinghua Bi, Dongmei Yan, Youcai Deng or Yonghui Lu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

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

Yuqing Lin, Biyun Yang, and Hailin Liu are co-first authors.

Supplementary information

ESM 1

(DOCX 2379 kb)

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

Lin, Y., Yang, B., Liu, H. et al. DNA demethylase Tet2 promotes the terminal maturation of natural killer cells. Immunol Res (2024). https://doi.org/10.1007/s12026-024-09506-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12026-024-09506-4

Keywords

Navigation