Abstract
Medullary thymic epithelial cells (mTECs) play a central role in the establishment of T cell central immunological tolerance by promiscuously expressing tissue-restricted antigens (TRAs) and presenting them to developing T cells, leading to deletion of T cells responding to self-antigens. However, molecular mechanisms especially epigenetic regulation of mTEC homeostasis and TRA expression remain elusive. Here we show that the H3K27 demethylase Kdm6b is essential to maintain the postnatal thymic medulla by promoting mTEC survival and regulating the expression of TRA genes. Moreover, mice lacking Kdm6b developed pathological autoimmune disorders. Mechanically, Kdm6b exerted its function by reducing repressive H3K27 trimethylation (H3K27me3) at the promoters of anti-apoptotic gene Bcl2 and a set of Aire-dependent TRA genes. Thus, our findings reveal a dual role of Kdm6b in the regulation of mTEC-mediated T cell central tolerance.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Rodewald HR. Thymus organogenesis. Annu Rev Immunol. 2008;26:355–88.
Anderson G, Takahama Y. Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol. 2012;33:256–63.
Aschenbrenner K, D’Cruz LM, Vollmann EH, Hinterberger M, Emmerich J, Swee LK, et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol. 2007;8:351–8.
Cowan JE, Parnell SM, Nakamura K, Caamano JH, Lane PJ, Jenkinson EJ, et al. The thymic medulla is required for Foxp3+ regulatory but not conventional CD4+ thymocyte development. J Exp Med. 2013;210:675–81.
Derbinski J, Schulte A, Kyewski B, Klein L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol. 2001;2:1032–9.
Klein L, Hinterberger M, Wirnsberger G, Kyewski B. Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol. 2009;9:833–44.
Takaba H, Morishita Y, Tomofuji Y, Danks L, Nitta T, Komatsu N, et al. Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell. 2015;163:975–87.
Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science. 2002;298:1395–401.
Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, et al. Positional cloning of the APECED gene. Nat Genet. 1997;17:393–8.
Rossi SW, Jenkinson WE, Anderson G, Jenkinson EJ. Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature. 2006;441:988–91.
Akiyama T, Shimo Y, Yanai H, Qin J, Ohshima D, Maruyama Y, et al. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity. 2008;29:423–37.
Hikosaka Y, Nitta T, Ohigashi I, Yano K, Ishimaru N, Hayashi Y, et al. The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity. 2008;29:438–50.
Rossi SW, Kim MY, Leibbrandt A, Parnell SM, Jenkinson WE, Glanville SH, et al. RANK signals from CD4(+)3(−) inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J Exp Med. 2007;204:1267–72.
Akiyama T, Maeda S, Yamane S, Ogino K, Kasai M, Kajiura F, et al. Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science. 2005;308:248–51.
Kajiura F, Sun S, Nomura T, Izumi K, Ueno T, Bando Y, et al. NF-kappa B-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner. J Immunol. 2004;172:2067–75.
Burkly L, Hession C, Ogata L, Reilly C, Marconi LA, Olson D, et al. Expression of relB is required for the development of thymic medulla and dendritic cells. Nature. 1995;373:531–6.
Zhang X, Wang H, Claudio E, Brown K, Siebenlist U. A role for the IkappaB family member Bcl-3 in the control of central immunologic tolerance. Immunity. 2007;27:438–52.
Takahama Y, Ohigashi I, Baik S, Anderson G. Generation of diversity in thymic epithelial cells. Nat Rev Immunol. 2017;17:295–305.
Atlasi Y, Stunnenberg HG. The interplay of epigenetic marks during stem cell differentiation and development. Nat Rev Genet. 2017;18:643–58.
Chuprin A, Avin A, Goldfarb Y, Herzig Y, Levi B, Jacob A, et al. The deacetylase Sirt1 is an essential regulator of Aire-mediated induction of central immunological tolerance. Nat Immunol. 2015;16:737–45.
Waterfield M, Khan IS, Cortez JT, Fan U, Metzger T, Greer A, et al. The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance. Nat Immunol. 2014;15:258–65.
Koh AS, Kuo AJ, Park SY, Cheung P, Abramson J, Bua D, et al. Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity. Proc Natl Acad Sci USA. 2008;105:15878–83.
Koh AS, Miller EL, Buenrostro JD, Moskowitz DM, Wang J, Greenleaf WJ, et al. Rapid chromatin repression by Aire provides precise control of immune tolerance. Nat Immunol. 2018;19:162–72.
Sansom SN, Shikama-Dorn N, Zhanybekova S, Nusspaumer G, Macaulay IC, Deadman ME, et al. Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia. Genome Res. 2014;24:1918–31.
Swigut T, Wysocka J. H3K27 demethylases, at long last. Cell. 2007;131:29–32.
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.
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.
Northrup D, Yagi R, Cui K, Proctor WR, Wang C, Placek K, et al. Histone demethylases UTX and JMJD3 are required for NKT cell development in mice. Cell Biosci. 2017;7:25.
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.
Ciofani M, Madar A, Galan C, Sellars M, Mace K, Pauli F, et al. A validated regulatory network for Th17 cell specification. Cell. 2012;151:289–303.
Burgold T, Voituron N, Caganova M, Tripathi PP, Menuet C, Tusi BK, et al. The H3K27 demethylase JMJD3 is required for maintenance of the embryonic respiratory neuronal network, neonatal breathing, and survival. Cell Rep. 2012;2:1244–58.
Zhang F, Xu L, Xu L, Xu Q, Li D, Yang Y, et al. JMJD3 promotes chondrocyte proliferation and hypertrophy during endochondral bone formation in mice. J Mol Cell Biol. 2015;7:23–34.
Gray DH, Seach N, Ueno T, Milton MK, Liston A, Lew AM, et al. Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood. 2006;108:3777–85.
Gray D, Abramson J, Benoist C, Mathis D. Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire. J Exp Med. 2007;204:2521–8.
Takahama Y. Journey through the thymus: stromal guides for T-cell development and selection. Nat Rev Immunol. 2006;6:127–35.
Jiang W, Anderson MS, Bronson R, Mathis D, Benoist C. Modifier loci condition autoimmunity provoked by Aire deficiency. J Exp Med. 2005;202:805–15.
Barradas M, Anderton E, Acosta JC, Li S, Banito A, Rodriguez-Niedenfuhr M, et al. Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes Dev. 2009;23:1177–82.
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.
Xing Y, Hogquist KA. Isolation, identification, and purification of murine thymic epithelial cells. J Vis Exp. 2014;8:e51780.
Acknowledgements
We thank Dr T. Boehm for the Foxn1-Cre transgenic mouse, Drs H. Wei, Y. Liu and B. Fu for their suggestions, B. Peng, B. Qian and Q. Jing for their support. This study was supported by grants from the National Program on Key Research (2018YFA0107500, 2016YFC1302400), the National Natural Science Foundation of China (91949102, 91742113, 31570902, 81771752 and 31370881) and the Guangzhou Key Medical Discipline Construction Project Fund.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Edited by D.R. Green
Supplementary information
Rights and permissions
About this article
Cite this article
Liu, Z., Zhang, H., Hu, Y. et al. Critical role of histone H3 lysine 27 demethylase Kdm6b in the homeostasis and function of medullary thymic epithelial cells. Cell Death Differ 27, 2843–2855 (2020). https://doi.org/10.1038/s41418-020-0546-8
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41418-020-0546-8
This article is cited by
-
JMJD3 upregulates ALOX5 to drive malignancy and concomitant ferroptosis sensitivity in gastric cancer
Cell Death & Disease (2025)
-
Epigenetic modifications in thymic epithelial cells: an evolutionary perspective for thymus atrophy
Clinical Epigenetics (2021)
-
Redressing the interactions between stem cells and immune system in tissue regeneration
Biology Direct (2021)
