[en] Central immune tolerance is established in the thymus for T cells via a complex selection process that involves interactions between CD4+CD8+ double-positive thymocytes and antigen-presenting cells. Cells that express antigen receptors interacting strongly with self peptide MHC complexes are deleted from the repertoire via activation-induced apoptosis, a process termed negative selection. Cells that express an appropriate signal are positively selected and mature into single positive naïve T cells, either CD4 or CD8 positive. The balance between positive and negative selection is thought to play a critical role in the elimination of self-reactive clones and in the establishment of central immune tolerance. We have recently reported that HDAC7, a class II histone deacetylase, is highly expressed in CD4+CD8+ double positive thymocytes. HDAC7 inhibits Nur77 expression, an orphan receptor involved in antigen-induced cell death and in negative selection. The inhibitory effect of HDAC7 on the Nur77 promoter is mediated via the transcription factor MEF2D. During T cell receptor activation, HDAC7 is exported from the nucleus leading to the derepression of Nur77 expression and the induction of apoptosis. These observations define HDAC7 as a regulator of Nur77 and apoptosis in developing thymocytes and indicate that HDAC7 is likely to play an important role in the control of central immune tolerance.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Verdin, Eric; Gladstone Institute of Virology and Immunology, Department of Medicine, University of California, San Francisco, PO Box 419100, San Francisco, CA 94141-9100, USA
Dequiedt, Franck ; Université de Liège - ULiège > Département des sciences de la vie > Génétique et biologie moléculaires animales ; Université de Liège - ULiège > GIGA > GIGA Molecular & Computational Biology - Gene Expression & Cancer
Kasler, Herb
Language :
English
Title :
HDAC7 regulates apoptosis in developing thymocytes.
Alberola-Ila J, Hernandez-Hoyos G 2003 The Ras/MAPK cascade and the control of positive selection. Immunol Rev 191:79-96
Alberola-Ila J, Hogquist KA, Swan KA, Bevan MJ, Perlmutter RM 1996 Positive and negative selection invoke distinct signaling pathways. J Exp Med 184:9-18
Anderson MS, Venanzi ES, Klein L et al 2002 Projection of an immunological self shadow within the thymus by the aire protein. Science 298:1395-1401
Blaeser F, Ho N, Prywes R, Chatila TA 2000 Ca(2+)-dependent gene expression mediated by MEF2 transcription factors. J Biol Chem 275:197-209
Buhlmann JE, Elkin SK, Sharpe AH 2003 A Role for the B7-1/B7-2:CD28/CTLA- 4 pathway during negative selection. J Immunol 170:5421-5428
Calnan BJ, Szychowski S, Chan FK, Cado D, Winoto A 1995 A role for the orphan steroid receptor Nur77 in apoptosis accompanying antigen-induced negative selection. Immunity 3:273-282
Cheng LE, Chan FK, Cado D, Winoto A 1997 Functional redundancy of the Nur77 and Nor-1 orphan steroid receptors in T-cell apoptosis. EMBO J 16:1865-1875
Dequiedt F, Kasler H, Fischle W et al 2003 HDAC7, a thymus-specific class II histone deacetylase, regulates Nur77 transcription and TCR-mediated apoptosis. Immunity 18:687-698
Downes M, Ordentlich P, Kao HY, Alvarez JG, Evans RM 2000 Identification of a nuclear domain with deacetylase activity. Proc Natl Acad Sci USA 97:10330-10335
Dressel U, Bailey PJ, Wang SC, Downes M, Evans RM, Muscat GE 2001 A dynamic role for HDAC7 in MEF2-mediated muscle differentiation. J Biol Chem 276:17007-17013
Esau C, Boes M, Youn HD, Tatterson L, Liu JO, Chen J 2001 Deletion of calcineurin and myocyte enhancer factor 2 (MEF2) binding domain of Cabin1 results in enhanced cytokine gene expression in T cells. J Exp Med 194:1449-1459
Fischer DD, Cai R, Bhatia U et al 2002 Isolation and characterization of a novel class II histone deacetylase, HDAC10. J Biol Chem 277:6656-6666
Fischle W, Emiliani S, Hendzel MJ et al 1999 A new family of human histone deacetylases related to Saccharomyces cerevisiae HDA1p. J Biol Chem 274:11713-11720
Fischle W, Kiermer V, Dequiedt F, Verdin E 2001a The emerging role of class II histone deacetylases. Biochem. Cell Biol 79:337-348
Fischle W, Dequiedt F, Fillion M, Hendzel MJ, Voelter W, Verdin E 2001b Human HDAC7 histone deacetylase activity is associated with HDAC3 in vivo. J Biol Chem 276:35826-35835
Fischle W, Dequiedt F, Hendzel MJ et al 2002 Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR. Mol Cell 9:45-57
Foy TM, Page DM, Waldschmidt TJ et al 1995 An essential role for gp39, the ligand for CD40, in thymic selection. J Exp Med 182:1377-1788
Gao L, Cueto MA, Asselbergs F, Atadja P 2002 Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J Biol Chem 277:25748-25755
Grozinger CM, Schreiber SL 2000 Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization. Proc Natl Acad Sci USA 97:7835-7840
Grozinger CM, Hassig CA, Schreiber SL 1999 Three proteins define a class of human histone deacetylases related to yeast Hda1p. Proc Natl Acad Sci USA 96:4868-4873
Guardiola AR, Yao TP 2002 Molecular cloning and characterization of a novel histone deacetylase HDAC10. J Biol Chem 277:3350-3356
Hazel TG, Nathans D, Lau LF 1988 A gene inducible by serum growth factors encodes a member of the steroid and thyroid hormone receptor superfamily. Proc Natl Acad Sci USA 85:8444-8448
Healy JI, Goodnow CC 1998 Positive versus negative signaling by lymphocyte antigen receptors. Annu Rev Immunol 16:645-670
Huang EY, Zhang J, Miska EA, Guenther MG, Kouzarides T, Lazar MA 2000 Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway. Genes Dev 14:45-54
Kao HY, Downes M, Ordentlich P, Evans RM 2000 Isolation of a novel histone deacetylase reveals that class I and class II deacetylases promote SMRT-mediated repression. Genes Dev 14:55-66
Kao HY, Verdel A, Tsai CC, Simon C, Juguilon H, Khochbin S 2001 Mechanism for nucleocytoplasmic shuttling of histone deacetylase 7. J Biol Chem 276:47496-47507
Kao HY, Lee CH, Komarov A, Han CC, Evans RM 2002 Isolation and characterization of mammalian HDAC10, a novel histone deacetylase. J Biol Chem 277:187-193
Kasler HG, Victoria J, Duramad O, Winoto A 2000 ERK5 is a novel type of mitogen-activated protein kinase containing a transcriptional activation domain. Mol Cell Biol 20:8382-8389
Kishimoto H, Sprent J 1999 Several different cell surface molecules control negative selection of medullary thymocytes. J Exp Med 190:65-73
Kishimoto H, Sprent J 2001 A defect in central tolerance in NOD mice. Nat Immunol 2:1025-1031
Lemercier C, Verdel A, Galloo B, Curtet S, Brocard MP, Khochbin S 2000 mHDA1/HDAC5 histone deacetylase interacts with and represses MEF2A transcriptional activity. J Biol Chem 275:15594-15599
Lu J, McKinsey TA, Zhang CL, Olson EN 2000 Regulation of skeletal myogenesis by association of the MEF2 transcription factor with class II histone deacetylases. Mol Cell 6:233-244
McKinsey TA, Zhang CL, Olson EN 2000a Activation of the myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14-3-3 to histone deacetylase 5. Proc Natl Acad Sci USA 97:14400-14405
McKinsey TA, Zhang CL, Lu J, Olson EN 2000b Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation. Nature 408:106-111
McKinsey TA, Zhang CL, Olson EN 2001 Identification of a signal-responsive nuclear export sequence in class II histone deacetylases. Mol Cell Biol 21:6312-6321
Milbrandt J 1988 Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene. Neuron 1:183-188
Miska EA, Karlsson C, Langley E, Nielsen SJ, Pines J, Kouzarides T 1999 HDAC4 deacetylase associates with and represses the MEF2 transcription factor. EMBO J 18:5099-5107
Miska EA, Langley E, Wolf D, Karlsson C, Pines J, Kouzarides T 2001 Differential localization of HDAC4 orchestrates muscle differentiation. Nucleic Acids Res 29:3439-3447
Ohashi PS 2002 T-cell signalling and autoimmunity: molecular mechanisms of disease. Nat Rev Immunol 2:427-438
Ohashi PS, DeFranco AL 2002 Making and breaking tolerance. Curr Opin Immunol 14:744-759
Page DM 1999 Cutting edge: thymic selection and autoreactivity are regulated by multiple coreceptors involved in T cell activation. J Immunol 163:3577-3581
Palmer E 2003 Negative selection - clearing out the bad apples from the T-cell repertoire. Nat Rev Immunol 3:383-391
Peterson P, Nagamine K, Scott H et al 1998 APECED: a monogenic autoimmune disease providing new clues to self-tolerance. Immunol Today 19:384-386
Punt JA, Osborne BA, Takahama Y, Sharrow SO, Singer A 1994 Negative selection of CD4+CD8+ thymocytes by T cell receptor-induced apoptosis requires a costimulatory signal that can be provided by CD28. J Exp Med 179:709-713
Rincon M, Whitmarsh A, Yang DD et al 1998 The JNK pathway regulates the in vivo deletion of immature CD4(+)CD8(+) thymocytes. J Exp Med 188:1817-1830
Ryseck RP, Macdonald-Bravo H, Mattei MG, Ruppert S, Bravo R 1989 Structure, mapping and expression of a growth factor inducible gene encoding a putative nuclear hormonal binding receptor. EMBO J 8:3327-3335
Sabapathy K, Kallunki T, David JP, Graef I, Karin M, Wagner EF 2001 c-Jun NH2-terminal kinase (JNK)1 and JNK2 have similar and stage-dependent roles in regulating T cell apoptosis and proliferation. J Exp Med 193:317-328
Sebzda E, Mariathasan S, Ohteki T, Jones R, Bachmann MF, Ohashi PS 1999 Selection of the T cell repertoire. Annu Rev Immunol 17:829-874
Sparrow DB, Miska EA, Langley E et al 1999 MEF-2 function is modified by a novel corepressor, MITR. EMBO J 18:5085-5098
Sprent J, Kishimoto H 2001 The thymus and central tolerance. Transplantation 72:S25-S28
Starr TK, Jameson SC, Hogquist KA 2003 Positive and negative selection of T cells. Annu Rev Immunol 21:139-176
Sugawara T, Moriguchi T, Nishida E, Takahama Y 1998 Differential roles of ERK and p38 MAP kinase pathways in positive and negative selection of T lymphocytes. Immunity 9:565-574
Suzuki A, Yamaguchi MT, Ohteki T et al 2001 T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 14:523-534
Swan KA, Alberola-Ila J, Gross JA et al 1995 Involvement of p21ras distinguishes positive and negative selection in thymocytes. EMBO J 14:276-285
Tong JJ, Liu J, Bertos NR, Yang XJ 2002 Identification of HDAC10, a novel class II human histone deacetylase containing a leucine-rich domain. Nucleic Acids Res 30:1114-1123
Verdel A, Khochbin S 1999 Identification of a new family of higher eukaryotic histone deacetylases. Coordinate expression of differentiation- dependent chromatin modifiers. J Biol Chem 274:2440-2445
Verdin E, Dequiedt F, Kasler HG 2003 Class II histone deacetylases: versatile regulators. Trends Genet 19:286-293
Wang AH, Yang XJ 2001 Histone deacetylase 4 possesses intrinsic nuclear import and export signals. Mol Cell Biol 21:5992-6005
Wang AH, Bertos NR, Vezmar M et al 1999 HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor. Mol Cell Biol 19:7816-7827
Wang AH, Kruhlak MJ, Wu J et al 2000 Regulation of histone deacetylase 4 by binding of 14-3-3 proteins. Mol Cell Biol 20:6904-6912
Woronicz JD, Calnan B, Ngo Y, Winoto A 1994 Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature 367:277-281
Woronicz JD, Lina A, Calnan BJ, Szychowski S, Cheng L, Winoto A 1995 Regulation of the Nur77 orphan steroid receptor in activation-induced apoptosis. Mol Cell Biol 15:6364-6376
Youn HD, Liu JO 2000 Cabin1 represses MEF2-dependent Nur77 expression and T cell apoptosis by controlling association of histone deacetylases and acetylases with MEF2. Immunity 13:85-94
Youn HD, Sun L, Prywes R, Liu JO 1999 Apoptosis of T cells mediated by Ca2+-induced release of the transcription factor MEF2. Science 286:790-793
Youn HD, Chatila TA, Liu JO 2000a Integration of calcineurin and MEF2 signals by the coactivator p300 during T-cell apoptosis. EMBO J 19:4323-4331
Youn H-D, Grozinger CM, Liu JO 2000b Calcium regulates transcriptional repression of myocyte enhancer factor 2 by histone deacetylase 4. J Biol Chem 275:22563-22567
Zhang CL, McKinsey TA, Olson EN 2001a The transcriptional corepressor MITR is a signal-responsive inhibitor of myogenesis. Proc Natl Acad Sci USA 98:7354-7359
Zhang CL, McKinsey TA, Lu J-r, Olson EN 2001b Association of COOH-terminal-binding protein (CtBP) and MEF2-interacting transcription repressor (MITR) contributes to transcriptional repression of the MEF2 transcription factor. J Biol Chem 276:35-39
Zhao X, Ito A, Kane CD et al 2001 The modular nature of histone deacetylase HDAC4 confers phosphorylation-dependent intracellular trafficking. J Biol Chem 276:35042-35048
