Histone Deacetylase 7 Functions as a Key Regulator of Genes Involved in both Positive and Negative Selection of Thymocytes

ABSTRACT Histone deacetylase 7 (HDAC7) is highly expressed in CD4+/CD8+ thymocytes and functions as a signal-dependent repressor of gene transcription during T-cell development. In this study, we expressed HDAC7 mutant proteins in a T-cell line and use DNA microarrays to identify transcriptional targets of HDAC7 in T cells. The changes in gene expression levels were compared to differential gene expression profiles associated with positive and negative thymic selection. This analysis reveals that HDAC7 regulates an extensive set of genes that are differentially expressed during both positive and negative thymic selection. Many of these genes play important functional roles in thymic selection, primarily via modulating the coupling between antigen receptor engagement and downstream signaling events. Consistent with the model that HDAC7 may play an important role in both positive and negative thymic selection, the expression of distinct HDAC7 mutants or the abrogation of HDAC7 expression can either enhance or inhibit the signal-dependent differentiation of a CD4+/CD8+ cell line.

[1]  E. Reinherz,et al.  Peptide-induced negative selection of thymocytes activates transcription of an NF-kappa B inhibitor. , 2002, Molecular cell.

[2]  L. Beretta,et al.  CD6: expression during development, apoptosis and selection of human and mouse thymocytes. , 2002, International immunology.

[3]  J. Trowsdale,et al.  Cotransfection of ICAM-1 and HLA-DR reconstitutes human antigen-presenting cell function in mouse L cells , 1989, Nature.

[4]  R. Flavell,et al.  The JNK Pathway Regulates the In Vivo Deletion of Immature CD4+CD8+ Thymocytes , 1998, The Journal of experimental medicine.

[5]  J. Bluestone,et al.  Ribp, a Novel Rlk/Txk- and Itk-Binding Adaptor Protein That Regulates T Cell Activation , 1999, The Journal of experimental medicine.

[6]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[7]  F. Alt,et al.  Bclx regulates the survival of double-positive thymocytes. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[8]  J. Sprent,et al.  Several Different Cell Surface Molecules Control Negative Selection of Medullary Thymocytes , 1999, The Journal of experimental medicine.

[9]  K. Nichols,et al.  Enhanced T cell responses due to diacylglycerol kinase ζ deficiency , 2003, Nature Immunology.

[10]  T. Zal,et al.  Antigen-presenting cells in the thymus that can negatively select MHC class II-restricted T cells recognizing a circulating self antigen. , 1997, Journal of Immunology.

[11]  P. Marks,et al.  Identification of a transcriptional repressor related to the noncatalytic domain of histone deacetylases 4 and 5. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[12]  C. Saint‐Ruf,et al.  Analysis and expression of a cloned pre-T cell receptor gene. , 1994, Science.

[13]  J. Kaye,et al.  Differentiation of an immature T cell line: A model of thymic positive selection , 1992, Cell.

[14]  A. Grinberg,et al.  CD5 Expression Is Developmentally Regulated By T Cell Receptor (TCR) Signals and TCR Avidity , 1998, The Journal of experimental medicine.

[15]  Sheryl K Elkin,et al.  A Role for the B7-1/B7-2:CD28/CTLA-4 Pathway During Negative Selection1 , 2003, The Journal of Immunology.

[16]  W. Alexander,et al.  Suppressor of Cytokine Signaling-1 Regulates Signaling in Response to Interleukin-2 and Other γc-dependent Cytokines in Peripheral T Cells* , 2003, Journal of Biological Chemistry.

[17]  Keji Zhao,et al.  Active chromatin domains are defined by acetylation islands revealed by genome-wide mapping. , 2005, Genes & development.

[18]  A. Ashworth,et al.  MKP5, a new member of the MAP kinase phosphatase family, which selectively dephosphorylates stress-activated kinases , 1999, Oncogene.

[19]  V. Kiermer,et al.  HDAC7, a thymus-specific class II histone deacetylase, regulates Nur77 transcription and TCR-mediated apoptosis. , 2003, Immunity.

[20]  B. Calnan,et al.  Regulation of the Nur77 orphan steroid receptor in activation-induced apoptosis , 1995, Molecular and cellular biology.

[21]  C. Thompson,et al.  Impaired negative selection in CD28-deficient mice. , 1998, Cellular immunology.

[22]  T. Mak,et al.  Roles of interferon-regulatory factors in T-helper-cell differentiation , 2005, Nature Reviews Immunology.

[23]  E. Olson,et al.  Protein Kinase D1 Phosphorylates HDAC7 and Induces Its Nuclear Export after T-cell Receptor Activation* , 2005, Journal of Biological Chemistry.

[24]  A. Tarakhovsky,et al.  Negative regulation of CD4 lineage development and responses by CD5. , 1999, Journal of immunology.

[25]  H. Gruffat,et al.  MEF2‐mediated recruitment of class II HDAC at the EBV immediate early gene BZLF1 links latency and chromatin remodeling , 2002, EMBO reports.

[26]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[27]  F. Chan,et al.  Functional redundancy of the Nur77 and Nor‐1 orphan steroid receptors in T‐cell apoptosis , 1997, The EMBO journal.

[28]  G. Freeman,et al.  Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation , 2000, The Journal of experimental medicine.

[29]  S. Schreiber,et al.  Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[30]  C. Park,et al.  Fine Tuning of TCR Signaling by CD5 , 2001, The Journal of Immunology.

[31]  J. Bluestone,et al.  CD28/B7 system of T cell costimulation. , 1996, Annual review of immunology.

[32]  A. Winoto,et al.  Distinct transcriptional programs in thymocytes responding to T cell receptor, Notch, and positive selection signals. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[33]  E. Miska,et al.  MEF‐2 function is modified by a novel co‐repressor, MITR , 1999, The EMBO journal.

[34]  S. Dower,et al.  Human Tribbles, a Protein Family Controlling Mitogen-activated Protein Kinase Cascades* , 2004, Journal of Biological Chemistry.

[35]  D. Chao,et al.  BCL-2 family: regulators of cell death. , 1998, Annual review of immunology.

[36]  B. Calnan,et al.  Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas , 1994, Nature.

[37]  Colin R. F. Monks,et al.  Three-dimensional segregation of supramolecular activation clusters in T cells , 1998, Nature.

[38]  G. Freeman,et al.  PD-L2 is a second ligand for PD-1 and inhibits T cell activation , 2001, Nature Immunology.

[39]  R. Flavell,et al.  Gadd45β and Gadd45γ are critical for regulating autoimmunity , 2005, The Journal of experimental medicine.

[40]  Barry I. Posner,et al.  Regulation of Histone Deacetylase 4 by Binding of 14-3-3 Proteins , 2000, Molecular and Cellular Biology.

[41]  F. Dequiedt,et al.  Class II histone deacetylases: versatile regulators. , 2003, Trends in genetics : TIG.

[42]  T. Sasaki,et al.  T cell-specific loss of Pten leads to defects in central and peripheral tolerance. , 2001, Immunity.

[43]  Thomas Seidl,et al.  Rules for Gene Usage Inferred from a Comparison of Large-Scale Gene Expression Profiles of T and B Lymphocyte Development 1 , 2003, The Journal of Immunology.

[44]  W. Alexander,et al.  Suppressor of cytokine signaling-1 regulates signaling in response to interleukin-2 and other gamma c-dependent cytokines in peripheral T cells. , 2003, The Journal of biological chemistry.

[45]  E. Reinherz,et al.  Gene expression analysis of thymocyte selection in vivo. , 2003, International immunology.

[46]  M. Rudnicki,et al.  Mutations in T-cell antigen receptor genes alpha and beta block thymocyte development at different stages. , 1992, Nature.

[47]  F. Dequiedt,et al.  Human HDAC7 Histone Deacetylase Activity Is Associated with HDAC3in Vivo * , 2001, The Journal of Biological Chemistry.

[48]  F. Dequiedt,et al.  Phosphorylation of histone deacetylase 7 by protein kinase D mediates T cell receptor–induced Nur77 expression and apoptosis , 2005, The Journal of experimental medicine.

[49]  A. Singer,et al.  Negative selection of CD4+CD8+ thymocytes by T cell receptor-induced apoptosis requires a costimulatory signal that can be provided by CD28 , 1994, The Journal of experimental medicine.

[50]  R. Flavell,et al.  The lack of NF-κB transactivation and PKCε expression in CD4+CD8+ thymocytes correlates with negative selection , 2000, Cell Death and Differentiation.

[51]  A. Heimberger,et al.  Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. , 1990, Science.

[52]  Nicola J. Rinaldi,et al.  Control of Pancreas and Liver Gene Expression by HNF Transcription Factors , 2004, Science.

[53]  E. Miska,et al.  Differential localization of HDAC4 orchestrates muscle differentiation. , 2001, Nucleic acids research.

[54]  S. Tonegawa,et al.  Mutations in T-cell antigen receptor genes α and β block thymocyte development at different stages , 1992, Nature.

[55]  P. Lapinski,et al.  Essential role of the T cell–specific adapter protein in the activation of LCK in peripheral T cells , 2006, The Journal of experimental medicine.

[56]  C. Benoist,et al.  Defective central tolerance induction in NOD mice: genomics and genetics. , 2005, Immunity.

[57]  T. Honjo,et al.  Facilitation of β Selection and Modification of Positive Selection in the Thymus of Pd-1–Deficient Mice , 2000, The Journal of experimental medicine.

[58]  A. Verdel,et al.  Mechanism for Nucleocytoplasmic Shuttling of Histone Deacetylase 7* , 2001, The Journal of Biological Chemistry.

[59]  K. Hogquist,et al.  The Regulated Expression of a Diverse Set of Genes during Thymocyte Positive Selection In Vivo1 , 2004, The Journal of Immunology.

[60]  A. Hayday,et al.  A novel disulfide-linked heterodimer on pre—T cells consists of the T cell receptor β chain and a 33 kd glycoprotein , 1993, Cell.

[61]  Tasuku Honjo,et al.  Absence of Programmed Death Receptor 1 Alters Thymic Development and Enhances Generation of CD4/CD8 Double-Negative TCR-Transgenic T Cells 1 , 2003, The Journal of Immunology.

[62]  E. Nishida,et al.  Differential roles of ERK and p38 MAP kinase pathways in positive and negative selection of T lymphocytes. , 1998, Immunity.

[63]  Y. Hayashi,et al.  CCR7-dependent cortex-to-medulla migration of positively selected thymocytes is essential for establishing central tolerance. , 2006, Immunity.

[64]  J. Tschopp,et al.  Fist/Hipk3 , 2000, The Journal of experimental medicine.

[65]  G. Linette,et al.  Bcl-2 is upregulated at the CD4+ CD8+ stage during positive selection and promotes thymocyte differentiation at several control points. , 1994, Immunity.

[66]  T. Cotter,et al.  JNK Regulates HIPK3 Expression and Promotes Resistance to Fas-mediated Apoptosis in DU 145 Prostate Carcinoma Cells* , 2004, Journal of Biological Chemistry.

[67]  A. Verdel,et al.  mHDA1/HDAC5 Histone Deacetylase Interacts with and Represses MEF2A Transcriptional Activity* , 2000, The Journal of Biological Chemistry.

[68]  M. Braddock,et al.  The transcriptional corepressor NAB2 blocks Egr-1-mediated growth factor activation and angiogenesis. , 2001, Biochemical and biophysical research communications.

[69]  A. Winoto,et al.  ERK5 Is a Novel Type of Mitogen-Activated Protein Kinase Containing a Transcriptional Activation Domain , 2000, Molecular and Cellular Biology.

[70]  J. Milbrandt,et al.  Thymocyte Development in Early Growth Response Gene 1-Deficient Mice1 , 2002, The Journal of Immunology.

[71]  A. Strasser,et al.  Activated T cell death in vivo mediated by proapoptotic bcl-2 family member bim. , 2002, Immunity.

[72]  R. Germain,et al.  Opening a Window on Thymic Positive Selection: Developmental Changes in the Influence of Cosignaling by Integrins and CD28 on Selection Events Induced by TCR Engagement , 2000, The Journal of Immunology.

[73]  Chun Li Zhang,et al.  Class II Histone Deacetylases Act as Signal-Responsive Repressors of Cardiac Hypertrophy , 2002, Cell.

[74]  D. Cantrell,et al.  Intracellular location and cell context-dependent function of protein kinase D. , 2003, Immunity.

[75]  Rick B. Vega,et al.  Protein Kinases C and D Mediate Agonist-Dependent Cardiac Hypertrophy through Nuclear Export of Histone Deacetylase 5 , 2004, Molecular and Cellular Biology.

[76]  G. Nolan,et al.  Production of high-titer helper-free retroviruses by transient transfection. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[77]  E. Olson,et al.  Histone Deacetylases 5 and 9 Govern Responsiveness of the Heart to a Subset of Stress Signals and Play Redundant Roles in Heart Development , 2004, Molecular and Cellular Biology.

[78]  F. Chan,et al.  A role for the orphan steroid receptor Nur77 in apoptosis accompanying antigen-induced negative selection. , 1995, Immunity.

[79]  Suresh Cuddapah,et al.  The genomic landscape of histone modifications in human T cells , 2006, Proceedings of the National Academy of Sciences.

[80]  T. Honjo,et al.  Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. , 1996, International immunology.

[81]  Xiaolong Liu,et al.  The zinc finger protein cKrox directs CD4 lineage differentiation during intrathymic T cell positive selection , 2005, Nature Immunology.

[82]  R. Flavell,et al.  The lack of NF-kappa B transactivation and PKC epsilon expression in CD4(+)CD8(+) thymocytes correlates with negative selection. , 2000, Cell death and differentiation.

[83]  W. Alexander,et al.  Suppressor of Cytokine Signaling-1 Has IFN-γ-Independent Actions in T Cell Homeostasis1 , 2003, The Journal of Immunology.

[84]  H. Heng,et al.  HDAC4, a Human Histone Deacetylase Related to Yeast HDA1, Is a Transcriptional Corepressor , 1999, Molecular and Cellular Biology.

[85]  M. Gadina,et al.  Cytohesin Binder and Regulator Augments T Cell Receptor-induced Nuclear Factor of Activated T Cells·AP-1 Activation through Regulation of the JNK Pathway* , 2006, Journal of Biological Chemistry.

[86]  A. Rajpal,et al.  Transcriptional activation of known and novel apoptotic pathways by Nur77 orphan steroid receptor , 2003, The EMBO journal.

[87]  John M. Shelton,et al.  Histone Deacetylase 4 Controls Chondrocyte Hypertrophy during Skeletogenesis , 2004, Cell.

[88]  G. Kersh,et al.  Control of Recent Thymic Emigrant Survival by Positive Selection Signals and Early Growth Response Gene 11 , 2005, The Journal of Immunology.

[89]  E. Olson,et al.  The transcriptional corepressor MITR is a signal-responsive inhibitor of myogenesis , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[90]  E. Olson,et al.  Histone Deacetylase 7 Maintains Vascular Integrity by Repressing Matrix Metalloproteinase 10 , 2006, Cell.

[91]  S. Hedrick,et al.  Isolation of the murine intercellular adhesion molecule 1 (ICAM-1) gene. ICAM-1 enhances antigen-specific T cell activation. , 1989, Journal of immunology.

[92]  K. Nakayama,et al.  Essential role for ZAP-70 in both positive and negative selection of thymocytes , 1995, Nature.

[93]  J. DeGregori,et al.  Characterization of Transcriptional Regulation During Negative Selection In Vivo1 , 2003, The Journal of Immunology.

[94]  R. Evans,et al.  Isolation of a novel histone deacetylase reveals that class I and class II deacetylases promote SMRT-mediated repression. , 2000, Genes & development.

[95]  K. Nichols,et al.  Enhanced T cell responses due to diacylglycerol kinase zeta deficiency. , 2003, Nature immunology.

[96]  D. Gray,et al.  CCR7 Signals Are Essential for Cortex–Medulla Migration of Developing Thymocytes , 2004, The Journal of experimental medicine.

[97]  E. Olson,et al.  Control of muscle development by dueling HATs and HDACs. , 2001, Current opinion in genetics & development.

[98]  D. M. Page.  Cutting edge: thymic selection and autoreactivity are regulated by multiple coreceptors involved in T cell activation. , 1999, Journal of immunology.

[99]  E. Reinherz,et al.  Peptide-Induced Negative Selection of Thymocytes Activates Transcription of an NF-ΚB Inhibitor , 2002 .

[100]  T. Honjo,et al.  Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4-CD8-) thymocytes. , 1996, International immunology.

[101]  R. Flavell,et al.  GADD45gamma mediates the activation of the p38 and JNK MAP kinase pathways and cytokine production in effector TH1 cells. , 2001, Immunity.

[102]  Robert D. Gerard,et al.  The Transcriptional Coactivator CAMTA2 Stimulates Cardiac Growth by Opposing Class II Histone Deacetylases , 2006, Cell.

[103]  U. Holmskov,et al.  The Scavenger Receptor Cysteine-Rich (SRCR) domain: an ancient and highly conserved protein module of the innate immune system. , 2004, Critical reviews in immunology.

[104]  E. Wagner,et al.  C-Jun Nh2-Terminal Kinase (Jnk)1 and Jnk2 Have Similar and Stage-Dependent Roles in Regulating T Cell Apoptosis and Proliferation , 2001, The Journal of experimental medicine.

[105]  E. Olson,et al.  Regulation of skeletal myogenesis by association of the MEF2 transcription factor with class II histone deacetylases. , 2000, Molecular cell.

[106]  M. Downes,et al.  A Dynamic Role for HDAC7 in MEF2-mediated Muscle Differentiation* , 2001, The Journal of Biological Chemistry.

[107]  S. Jameson,et al.  Selective development of CD4+ T cells in transgenic mice expressing a class II MHC-restricted antigen receptor , 1989, Nature.