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Zhang H, Hu Y, Liu D, et al. The histone demethylase Kdm6b regulates the maturation and cytotoxicity of TCRαβ. Cell Death Differ. 2022;doi: 10.1038/s41418-021-00921-w.
Zhang, H., Hu, Y., Liu, D., Liu, Z., Xie, N., Liu, S., Zhang, J., Jiang, Y., Li, C., Wang, Q., Chen, X., Ye, D., Sun, D., Zhai, Y., Yan, X., Liu, Y., Chen, C. D., Huang, X., Eugene Chin, Y., Shi, Y., Wu, B., & Zhang, X. (2022). The histone demethylase Kdm6b regulates the maturation and cytotoxicity of TCRαβ. Cell death and differentiation, . https://doi.org/10.1038/s41418-021-00921-w
Zhang, Haohao, et al. "The histone demethylase Kdm6b regulates the maturation and cytotoxicity of TCRαβ." Cell death and differentiation vol. (2022). doi: https://doi.org/10.1038/s41418-021-00921-w
Zhang H, Hu Y, Liu D, Liu Z, Xie N, Liu S, Zhang J, Jiang Y, Li C, Wang Q, Chen X, Ye D, Sun D, Zhai Y, Yan X, Liu Y, Chen CD, Huang X, Eugene Chin Y, Shi Y, Wu B, Zhang X. The histone demethylase Kdm6b regulates the maturation and cytotoxicity of TCRαβ. Cell Death Differ. 2022 Jan 09; doi: 10.1038/s41418-021-00921-w. Epub 2022 Jan 09. PMID: 34999729.
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Cell Death Differ. 2022 Jan 09; doi: 10.1038/s41418-021-00921-w. Epub 2022 Jan 09.

The histone demethylase Kdm6b regulates the maturation and cytotoxicity of TCRαβ.

Cell death and differentiation

Haohao Zhang, Yiming Hu, Dandan Liu, Zhi Liu, Ningxia Xie, Sanhong Liu, Jie Zhang, Yuhang Jiang, Cuifeng Li, Qi Wang, Xi Chen, Deji Ye, Donglin Sun, Yujia Zhai, Xinhui Yan, Yongzhong Liu, Charlie Degui Chen, Xingxu Huang, Y Eugene Chin, Yufang Shi, Baojin Wu, Xiaoren Zhang

Affiliations

  1. Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China.
  2. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China.
  3. Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 201203, Shanghai, China.
  4. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200032, Shanghai, China.
  5. State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China.
  6. Institutes of Biology and Medical Sciences, Soochow University Medical College, 215000, Suzhou, China.
  7. Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, 200031, Shanghai, China. [email protected].
  8. Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China. [email protected].
  9. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China. [email protected].

PMID: 34999729 DOI: 10.1038/s41418-021-00921-w

Abstract

Intestinal intraepithelial lymphocytes (IELs) are distributed along the length of the intestine and are considered the frontline of immune surveillance. The precise molecular mechanisms, especially epigenetic regulation, of their development and function are poorly understood. The trimethylation of histone 3 at lysine 27 (H3K27Me3) is a kind of histone modifications and associated with gene repression. Kdm6b is an epigenetic enzyme responsible for the demethylation of H3K27Me3 and thus promotes gene expression. Here we identified Kdm6b as an important intracellular regulator of small intestinal IELs. Mice genetically deficient for Kdm6b showed greatly reduced numbers of TCRαβ

© 2021. The Author(s).

References

  1. Agace WW, McCoy KD. Regionalized Development and Maintenance of the Intestinal Adaptive Immune Landscape. Immunity 2017;46:532–48. - PubMed
  2. Van Kaer L, Algood HMS, Singh K, Parekh VV, Greer MJ, Piazuelo MB, et al. CD8alphaalpha(+) innate-type lymphocytes in the intestinal epithelium mediate mucosal immunity. Immunity 2014;41:451–64. - PubMed
  3. McDonald BD, Jabri B, Bendelac A. Diverse developmental pathways of intestinal intraepithelial lymphocytes. Nat Rev Immunol. 2018;18:514–25. - PubMed
  4. Cheroutre H, Lambolez F. The thymus chapter in the life of gut-specific intra epithelial lymphocytes. Curr Opin Immunol. 2008;20:185–91. - PubMed
  5. Pobezinsky LA, Angelov GS, Tai X, Jeurling S, Van Laethem F, Feigenbaum L, et al. Clonal deletion and the fate of autoreactive thymocytes that survive negative selection. Nat Immunol. 2012;13:569–78. - PubMed
  6. Olivares-Villagomez D, Van Kaer L. Intestinal Intraepithelial Lymphocytes: Sentinels of the Mucosal Barrier. Trends Immunol. 2018;39:264–75. - PubMed
  7. Agace W. Generation of gut-homing T cells and their localization to the small intestinal mucosa. Immunol Lett. 2010;128:21–3. - PubMed
  8. El-Asady R, Yuan R, Liu K, Wang D, Gress RE, Lucas PJ, et al. TGF-{beta}-dependent CD103 expression by CD8(+) T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease. J Exp Med. 2005;201:1647–57. - PubMed
  9. Ericsson A, Svensson M, Arya A, Agace WW. CCL25/CCR9 promotes the induction and function of CD103 on intestinal intraepithelial lymphocytes. Eur J Immunol. 2004;34:2720–9. - PubMed
  10. Ma LJ, Acero LF, Zal T, Schluns KS. Trans-presentation of IL-15 by intestinal epithelial cells drives development of CD8alphaalpha IELs. J Immunol. 2009;183:1044–54. - PubMed
  11. Yu Q, Tang C, Xun S, Yajima T, Takeda K, Yoshikai Y. MyD88-dependent signaling for IL-15 production plays an important role in maintenance of CD8 alpha alpha TCR alpha beta and TCR gamma delta intestinal intraepithelial lymphocytes. J Immunol. 2006;176:6180–5. - PubMed
  12. Klose CS, Blatz K, d’Hargues Y, Hernandez PP, Kofoed-Nielsen M, Ripka JF, et al. The transcription factor T-bet is induced by IL-15 and thymic agonist selection and controls CD8alphaalpha(+) intraepithelial lymphocyte development. Immunity 2014;41:230–43. - PubMed
  13. Jiang W, Wang X, Zeng B, Liu L, Tardivel A, Wei H, et al. Recognition of gut microbiota by NOD2 is essential for the homeostasis of intestinal intraepithelial lymphocytes.J Exp Med. 2013;210:2465–76. - PubMed
  14. Leishman AJ, Gapin L, Capone M, Palmer E, MacDonald HR, Kronenberg M, et al. Precursors of functional MHC class I- or class II-restricted CD8alphaalpha(+) T cells are positively selected in the thymus by agonist self-peptides. Immunity 2002;16:355–64. - PubMed
  15. Yamagata T, Mathis D, Benoist C. Self-reactivity in thymic double-positive cells commits cells to a CD8 alpha alpha lineage with characteristics of innate immune cells. Nat Immunol. 2004;5:597–605. - PubMed
  16. Dalessandri T, Crawford G, Hayes M, Castro Seoane R, Strid J. IL-13 from intraepithelial lymphocytes regulates tissue homeostasis and protects against carcinogenesis in the skin. Nat Commun. 2016;7:12080. - PubMed
  17. Mikulak J, Oriolo F, Bruni E, Roberto A, Colombo FS, Villa A, et al. NKp46-expressing human gut-resident intraepithelial Vdelta1 T cell subpopulation exhibits high antitumor activity against colorectal cancer. JCI insight. 2019;4:e125884. - PubMed
  18. Denning TL, Granger SW, Mucida D, Graddy R, Leclercq G, Zhang W, et al. Mouse TCRalphabeta+CD8alphaalpha intraepithelial lymphocytes express genes that down-regulate their antigen reactivity and suppress immune responses. J Immunol. 2007;178:4230–9. - PubMed
  19. Poussier P, Ning T, Banerjee D, Julius M. A unique subset of self-specific intraintestinal T cells maintains gut integrity. J Exp Med. 2002;195:1491–7. - PubMed
  20. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, et al. High-resolution profiling of histone methylations in the human genome. Cell 2007;129:823–37. - PubMed
  21. Bosselut R. Pleiotropic Functions of H3K27Me3 Demethylases in Immune Cell Differentiation. Trends Immunol. 2016;37:102–13. - PubMed
  22. Agger K, Cloos PA, Christensen J, Pasini D, Rose S, Rappsilber J, et al. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 2007;449:731–4. - PubMed
  23. Yamada T, Nabe S, Toriyama K, Suzuki J, Inoue K, Imai Y, et al. Histone H3K27 Demethylase Negatively Controls the Memory Formation of Antigen-Stimulated CD8(+) T Cells. J Immunol. 2019;202:1088–98. - PubMed
  24. Li J, Hardy K, Olshansky M, Barugahare A, Gearing LJ, Prier JE, et al. KDM6B-dependent chromatin remodeling underpins effective virus-specific CD8(+) T cell differentiation. Cell reports. 2021;34:108839. - PubMed
  25. Xu TH, Schutte A, Jimenez L, Goncalves ANA, Keller A, Pipkin ME, et al. Kdm6b Regulates the Generation of Effector CD8(+) T Cells by Inducing Chromatin Accessibility in Effector-Associated Genes. J Immunol. 2021;206:2170–83. - PubMed
  26. Fu C, Li Q, Zou J, Xing C, Luo M, Yin B, et al. JMJD3 regulates CD4 T cell trafficking by targeting actin cytoskeleton regulatory gene Pdlim4. J Clin Investig. 2019;130:4745–57. - PubMed
  27. Manna S, Kim JK, Bauge C, Cam M, Zhao Y, Shetty J, et al. Histone H3 Lysine 27 demethylases Jmjd3 and Utx are required for T-cell differentiation. Nat Commun. 2015;6:8152. - PubMed
  28. Liu Z, Cao W, Xu L, Chen X, Zhan Y, Yang Q, et al. The histone H3 lysine-27 demethylase Jmjd3 plays a critical role in specific regulation of Th17 cell differentiation. J Mol cell Biol. 2015;7:505–16. - PubMed
  29. Beyaz S, Kim JH, Pinello L, Xifaras ME, Hu Y, Huang J, et al. The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells. Nat Immunol. 2017;18:184–95. - PubMed
  30. Howson LJ, Li J, von Borstel A, Barugahare A, Mak JYW, Fairlie DP, et al. Mucosal-Associated Invariant T Cell Effector Function Is an Intrinsic Cell Property That Can Be Augmented by the Metabolic Cofactor alpha-Ketoglutarate. J Immunol. 2021;206:1425–35. - PubMed
  31. Pereira F, Barbachano A, Silva J, Bonilla F, Campbell MJ, Munoz A, et al. KDM6B/JMJD3 histone demethylase is induced by vitamin D and modulates its effects in colon cancer cells. Hum Mol Genet. 2011;20:4655–65. - PubMed
  32. Bruce D, Cantorna MT. Intrinsic requirement for the vitamin D receptor in the development of CD8alphaalpha-expressing T cells. J Immunol. 2011;186:2819–25. - PubMed
  33. Reis BS, Hoytema van Konijnenburg DP, Grivennikov SI, Mucida D. Transcription factor T-bet regulates intraepithelial lymphocyte functional maturation. Immunity 2014;41:244–56. - PubMed
  34. Nakajima K, Maekawa Y, Kataoka K, Ishifune C, Nishida J, Arimochi H, et al. The ARNT-STAT3 axis regulates the differentiation of intestinal intraepithelial TCRalphabeta(+)CD8alphaalpha(+) cells. Nat Commun. 2013;4:2112. - PubMed
  35. Konkel JE, Maruyama T, Carpenter AC, Xiong Y, Zamarron BF, Hall BE, et al. Control of the development of CD8alphaalpha+ intestinal intraepithelial lymphocytes by TGF-beta. Nat Immunol. 2011;12:312–9. - PubMed
  36. Jiang W, Ferrero I, Laurenti E, Trumpp A, MacDonald HR. c-Myc controls the development of CD8alphaalpha TCRalphabeta intestinal intraepithelial lymphocytes from thymic precursors by regulating IL-15-dependent survival. Blood 2010;115:4431–8. - PubMed
  37. Sun L, Li T, Tang H, Yu K, Ma Y, Yu M, et al. Intestinal Epithelial Cells-Derived Hypoxia-Inducible Factor-1alpha Is Essential for the Homeostasis of Intestinal Intraepithelial Lymphocytes. Front Immunol. 2019;10:806. - PubMed
  38. Ruscher R, Kummer RL, Lee YJ, Jameson SC, Hogquist KA. CD8alphaalpha intraepithelial lymphocytes arise from two main thymic precursors. Nat Immunol. 2017;18:771–9. - PubMed
  39. Ellmeier W, Sunshine MJ, Losos K, Hatam F, Littman DR. An enhancer that directs lineage-specific expression of CD8 in positively selected thymocytes and mature T cells. Immunity 1997;7:537–47. - PubMed
  40. Gulich AF, Preglej T, Hamminger P, Alteneder M, Tizian C, Orola MJ, et al. Differential Requirement of Cd8 Enhancers E8(I) and E8(VI) in Cytotoxic Lineage T Cells and in Intestinal Intraepithelial Lymphocytes. Frontiers in immunology. 2019;10:409. - PubMed
  41. Prier JE, Li J, Gearing LJ, Olshansky M, Sng XYX, Hertzog PJ, et al. Early T-BET Expression Ensures an Appropriate CD8(+) Lineage-Specific Transcriptional Landscape after Influenza A Virus Infection. J Immunol. 2019;203:1044–54. - PubMed
  42. Svotelis A, Bianco S, Madore J, Huppe G, Nordell-Markovits A, Mes-Masson AM, et al. H3K27 demethylation by JMJD3 at a poised enhancer of anti-apoptotic gene BCL2 determines ERalpha ligand dependency. EMBO J. 2011;30:3947–61. - PubMed
  43. Liu RB, Engels B, Schreiber K, Ciszewski C, Schietinger A, Schreiber H, et al. IL-15 in tumor microenvironment causes rejection of large established tumors by T cells in a noncognate T cell receptor-dependent manner. Proc Natl Acad Sci USA. 2013;110:8158–63. - PubMed
  44. Shires J, Theodoridis E, Hayday AC. Biological insights into TCRgammadelta+ and TCRalphabeta+ intraepithelial lymphocytes provided by serial analysis of gene expression (SAGE). Immunity 2001;15:419–34. - PubMed
  45. Tu MM, Mahmoud AB, Wight A, Mottashed A, Belanger S, Rahim MM, et al. Ly49 family receptors are required for cancer immunosurveillance mediated by natural killer cells. Cancer Res. 2014;74:3684–94. - PubMed
  46. Roberts AI, O’Connell SM, Biancone L, Brolin RE, Ebert EC. Spontaneous cytotoxicity of intestinal intraepithelial lymphocytes: clues to the mechanism. Clin Exp Immunol. 1993;94:527–32. - PubMed
  47. Lin T, Brunner T, Tietz B, Madsen J, Bonfoco E, Reaves M, et al. Fas ligand- mediated killing by intestinal intraepithelial lymphocytes. Participation in intestinal graft-versus-host disease. J Clin Investig. 1998;101:570–7. - PubMed
  48. Ostanin DV, Brown CM, Gray L, Bharwani S, Grisham MB. Evaluation of the immunoregulatory activity of intraepithelial lymphocytes in a mouse model of chronic intestinal inflammation. Int Immunol. 2010;22:927–39. - PubMed
  49. Ntziachristos P, Tsirigos A, Welstead GG, Trimarchi T, Bakogianni S, Xu LY, et al. Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature 2014;514:513−+. - PubMed
  50. Van der Meulen J, Sanghvi V, Mavrakis K, Durinck K, Fang F, Matthijssens F, et al. The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia. Blood 2015;125:13–21. - PubMed
  51. Chen J, Xu X, Li Y, Li F, Zhang JJ, Xu Q, et al. Kdm6a suppresses the alternative activation of macrophages and impairs energy expenditure in obesity. Cell Death Differ. 2021;28:1688–704. - PubMed
  52. Satoh T, Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y, et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol. 2010;11:936–44. - PubMed
  53. Yue TT, Sun F, Wang FX, Yang CL, Luo JH, Rong SJ, et al. MBD2 acts as a repressor to maintain the homeostasis of the Th1 program in type 1 diabetes by regulating the STAT1-IFN-gamma axis. Cell Death Differ. 2021. https://doi.org/10.1038/s41418-021-00852-6 . Online ahead of print. - PubMed

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