Nuclear export of histone deacetylase 7 during thymic selection is required for immune self-tolerance.

[en] Histone deacetylase 7 (HDAC7) is a T-cell receptor (TCR) signal-dependent regulator of differentiation that is highly expressed in CD4/CD8 double-positive (DP) thymocytes. Here, we examine the effect of blocking TCR-dependent nuclear export of HDAC7 during thymic selection, through expression of a signal-resistant mutant of HDAC7 (HDAC7-DeltaP) in thymocytes. We find that HDAC7-DeltaP transgenic thymocytes exhibit a profound block in negative thymic selection, but can still undergo positive selection, resulting in the escape of autoreactive T cells into the periphery. Gene expression profiling reveals a comprehensive suppression of the negative selection-associated gene expression programme in DP thymocytes, associated with a defect in the activation of MAP kinase pathways by TCR signals. The consequence of this block in vivo is a lethal autoimmune syndrome involving the exocrine pancreas and other abdominal organs. These experiments establish a novel molecular model of autoimmunity and cast new light on the relationship between thymic selection and immune self-tolerance.

Research center :

Giga-Cancer - ULiège

Disciplines :

Oncology
Biochemistry, biophysics & molecular biology

Author, co-author :

Kasler, Herbert G.

Lim, Hyung W.

Mottet, Denis ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases

Collins, Amy M.

Lee, Intelly S.

Verdin, Eric

Language :

English

Title :

Nuclear export of histone deacetylase 7 during thymic selection is required for immune self-tolerance.

Publication date :

2012

Journal title :

EMBO Journal

ISSN :

0261-4189

eISSN :

1460-2075

Publisher :

Wiley-Blackwell, United States

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Herbert G Kasler, Hyung W Lim, Denis Mottet : These authors contributed equally to this work.

Available on ORBi :

since 21 November 2012

Statistics

Number of views

68 (1 by ULiège)

Number of downloads

0 (0 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

Bibliography

Anderson MS, Todd JK, Glode MP (2005a) Delayed diagnosis of Kawasaki syndrome: an analysis of the problem. Pediatrics 115: e428-e433
Anderson MS, Venanzi ES, Chen Z, Berzins SP, Benoist C, Mathis D (2005b) The cellular mechanism of Aire control of T cell tolerance. Immunity 23: 227-239 (Pubitemid 41169291)
Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D (2002) Projection of an immunological self shadow within the thymus by the aire protein. Science 298: 1395-1401 (Pubitemid 35346134)
Barnden MJ, Allison J, Heath WR, Carbone FR (1998) Defective TCR expression in transgenic mice constructed using cDNA-based alpha-and beta-chain genes under the control of heterologous regulatory elements. Immunol Cell Biol 76: 34-40 (Pubitemid 28194695)
Bennett CL, Brunkow ME, Ramsdell F, O'Briant KC, Zhu Q, Fuleihan RL, Shigeoka AO, Ochs HD, Chance PF (2001a) A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA-4AAU GAA) leads to the IPEX syndrome. Immunogenetics 53: 435-439 (Pubitemid 32906982)
Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD (2001b) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27: 20-21 (Pubitemid 32044513)
Bluthmann H, Kisielow P, Uematsu Y, Malissen M, Krimpenfort P, Berns A, von Boehmer H, Steinmetz M (1988) T-cell-specific deletion of T-cell receptor transgenes allows functional rearrangement of endogenous alpha-and beta-genes. Nature 334: 156-159
Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F, Adams JM, Strasser A (1999) Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286: 1735-1738 (Pubitemid 129515880)
Bouillet P, Purton JF, Godfrey DI, Zhang LC, Coultas L, Puthalakath H, Pellegrini M, Cory S, Adams JM, Strasser A (2002) BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415: 922-926 (Pubitemid 34174755)
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
Chang S, McKinsey TA, Zhang CL, Richardson JA, Hill JA, Olson EN (2004) Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development. Mol Cell Biol 24: 8467-8476 (Pubitemid 39245069)
Chang S, Young BD, Li S, Qi X, Richardson JA, Olson EN (2006) Histone deacetylase 7 maintains vascular integrity by repressing matrix metalloproteinase 10. Cell 126: 321-334 (Pubitemid 44092958)
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 (Pubitemid 27170948)
Daniels MA, Teixeiro E, Gill J, Hausmann B, Roubaty D, Holmberg K, Werlen G, Hollander GA, Gascoigne NR, Palmer E (2006) Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature 444: 724-729 (Pubitemid 44949596)
Dequiedt F, Kasler H, Fischle W, Kiermer V, Weinstein M, Herndier BG, Verdin E (2003) HDAC7, a thymus-specific class II histone deacetylase, regulates Nur77 transcription and TCR-mediated apoptosis. Immunity 18: 687-698 (Pubitemid 36588585)
Fife BT, Bluestone JA (2008) Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev 224: 166-182
Gehart H, Kumpf S, Ittner A, Ricci R (2010) MAPK signalling in cellular metabolism: stress or wellness? EMBO Rep 11: 834-840
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 (Pubitemid 30460734)
Hildeman DA, Zhu Y, Mitchell TC, Bouillet P, Strasser A, Kappler J, Marrack P (2002) Activated T cell death in vivo mediated by proapoptotic bcl-2 family member bim. Immunity 16: 759-767 (Pubitemid 34786475)
Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299: 1057-1061 (Pubitemid 36222930)
Hutcheson J, Scatizzi JC, Siddiqui AM, Haines 3rd GK, Wu T, Li QZ, Davis LS, Mohan C, Perlman H (2008) Combined deficiency of proapoptotic regulators Bim and Fas results in the early onset of systemic autoimmunity. Immunity 28: 206-217 (Pubitemid 351215233)
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
Kasler HG, Young BD, Mottet D, Lim HW, Collins AM, Olson EN, Verdin E (2011) Histone deacetylase 7 regulates cell survival and TCR signaling in CD4/CD8 double-positive thymocytes. J Immunol 186: 4782-4793
Keir ME, Freeman GJ, Sharpe AH (2007) PD-1 regulates self-reactive CD8\+ T cell responses to antigen in lymph nodes and tissues. J Immunol 179: 5064-5070
Lu J, McKinsey TA, Nicol RL, Olson EN (2000) Signal-dependent activation of the MEF2 transcription factor by dissociation from histone deacetylases. Proc Natl Acad Sci USA 97: 4070-4075 (Pubitemid 30226088)
McKinsey TA, Zhang CL, Olson EN (2001) Identification of a signalresponsive nuclear export sequence in class II histone deacetylases. Mol Cell Biol 21: 6312-6321 (Pubitemid 34263529)
Meagher C, Tang Q, Fife BT, Bour-Jordan H, Wu J, Pardoux C, Bi M, Melli K, Bluestone JA (2008) Spontaneous development of a pancreatic exocrine disease in CD28-deficient NOD mice. J Immunol 180: 7793-7803
Mihaylova MM, Vasquez DS, Ravnskjaer K, Denechaud PD, Yu RT, Alvarez JG, Downes M, Evans RM, Montminy M, Shaw RJ (2011) Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell 145: 607-621
Mosenden R, Tasken K (2011) Cyclic AMP-mediated immune regulation-overview of mechanisms of action in T cells. Cell Signal 23: 1009-1016
Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJ, Lalioti MD, Mullis PE, Antonarakis SE, Kawasaki K, Asakawa S, Ito F, Shimizu N (1997) Positional cloning of the APECED gene. Nat Genet 17: 393-398 (Pubitemid 27518386)
Navarro MN, Goebel J, Feijoo-Carnero C, Morrice N, Cantrell DA (2011) Phosphoproteomic analysis reveals an intrinsic pathway for the regulation of histone deacetylase 7 that controls the function of cytotoxic T lymphocytes. Nat Immunol 12: 352-361
Niki S, Oshikawa K, Mouri Y, Hirota F, Matsushima A, Yano M, Han H, Bando Y, Izumi K, Matsumoto M, Nakayama KI, Kuroda N (2006) Alteration of intra-pancreatic target-organ specificity by abrogation of Aire in NOD mice. J Clin Invest 116: 1292-1301
Parra M, Mahmoudi T, Verdin E (2007) Myosin phosphatase dephosphorylates HDAC7, controls its nucleocytoplasmic shuttling, and inhibits apoptosis in thymocytes. Genes Dev 21: 638-643 (Pubitemid 46440285)
Peter PS, Brady JE, Yan L, Chen W, Engelhardt S, Wang Y, Sadoshima J, Vatner SF, Vatner DE (2007) Inhibition of p38 alpha MAPK rescues cardiomyopathy induced by overexpressed beta 2-adrenergic receptor, but not beta 1-adrenergic receptor. J Clin Invest 117: 1335-1343 (Pubitemid 46718421)
Ramsey C, Winqvist O, Puhakka L, Halonen M, Moro A, Kampe O, Eskelin P, Pelto-Huikko M, Peltonen L (2002) Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum Mol Genet 11: 397-409 (Pubitemid 34213613)
Rincon M, Whitmarsh A, Yang DD, Weiss L, Derijard B, Jayaraj P, Davis RJ, Flavell RA (1998) The JNK pathway regulates the In vivo deletion of immature CD4(\+)CD8(\+) thymocytes. J Exp Med 188: 1817-1830 (Pubitemid 28536769)
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 (Pubitemid 32524515)
Starr TK, Jameson SC, Hogquist KA (2003) Positive and negative selection of T cells. Annu Rev Immunol 21: 139-176 (Pubitemid 37174529)
Staton TL, Lazarevic V, Jones DC, Lanser AJ, Takagi T, Ishii S, Glimcher LH (2011) Dampening of death pathways by schnurri-2 is essential for T-cell development. Nature 472: 105-109
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 (Pubitemid 28499207)
Tanaka S, Maeda S, Hashimoto M, Fujimori C, Ito Y, Teradaira S, Hirota K, Yoshitomi H, Katakai T, Shimizu A, Nomura T, Sakaguchi N, Sakaguchi S (2010) Graded attenuation of TCR signaling elicits distinct autoimmune diseases by altering thymic T cell selection and regulatory T cell function. J Immunol 185: 2295-2305
Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3: 541-547
Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 98: 5116-5121 (Pubitemid 32397092)
Vega RB, Matsuda K, Oh J, Barbosa AC, Yang X, Meadows E, McAnally J, Pomajzl C, Shelton JM, Richardson JA, Karsenty G, Olson EN (2004) Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Cell 119: 555-566 (Pubitemid 39482354)
Wang AH, Kruhlak MJ, Wu J, Bertos NR, Vezmar M, Posner BI, Bazett-Jones DP, Yang XJ (2000) Regulation of histone deacetylase 4 by binding of 14-3-3 proteins. Mol Cell Biol 20: 6904-6912
Wang B, Moya N, Niessen S, Hoover H, Mihaylova MM, Shaw RJ, Yates 3rd JR, Fischer WH, Thomas JB, Montminy M (2011) A hormone-dependent module regulating energy balance. Cell 145: 596-606
Weant AE, Michalek RD, Khan IU, Holbrook BC, Willingham MC, Grayson JM (2008) Apoptosis regulators Bim and Fas function concurrently to control autoimmunity and CD8\+ T cell contraction. Immunity 28: 218-230 (Pubitemid 351215232)
Woronicz JD, Calnan B, Ngo V, Winoto A (1994) Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature 367: 277-281 (Pubitemid 24051144)
Zhang CL, McKinsey TA, Chang S, Antos CL, Hill JA, Olson EN (2002) Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110: 479-488 (Pubitemid 35232291)
Zhou X, Richon VM, Rifkind RA, Marks PA (2000) Identification of a transcriptional repressor related to the noncatalytic domain of histone deacetylases 4 and 5. Proc Natl Acad Sci USA 97: 1056-1061 (Pubitemid 30080811)
Zucchelli S, Holler P, Yamagata T, Roy M, Benoist C, Mathis D (2005) Defective central tolerance induction in NOD mice: genomics and genetics. Immunity 22: 385-396 (Pubitemid 40387479)