Regulation of interferon-gamma during innate and adaptive immune responses.

Interferon-gamma (IFN-gamma) is crucial for immunity against intracellular pathogens and for tumor control. However, aberrant IFN-gamma expression has been associated with a number of autoinflammatory and autoimmune diseases. This cytokine is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by Th1 CD4 and CD8 cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops. Herein, we briefly review the functions of IFN-gamma, the cells that produce it, the cell extrinsic signals that induce its production and influence the differentiation of naïve T cells into IFN-gamma-producing effector T cells, and the signaling pathways and transcription factors that facilitate, induce, or repress production of this cytokine. We then review and discuss recent insights regarding the molecular regulation of IFN-gamma, focusing on work that has led to the identification and characterization of distal regulatory elements and epigenetic modifications with the IFN-gamma locus (Ifng) that govern its expression. The epigenetic modifications and three-dimensional structure of the Ifng locus in naive CD4 T cells, and the modifications they undergo as these cells differentiate into effector T cells, suggest a model whereby the chromatin architecture of Ifng is poised to facilitate either rapid opening or silencing during Th1 or Th2 differentiation, respectively.

[1]  L. Harrington,et al.  Expanding the effector CD4 T-cell repertoire: the Th17 lineage. , 2006, Current opinion in immunology.

[2]  H. Hirai,et al.  Delta1-Notch3 interactions bias the functional differentiation of activated CD4+ T cells. , 2003, Immunity.

[3]  G. Felsenfeld,et al.  Insulators: exploiting transcriptional and epigenetic mechanisms , 2006, Nature Reviews Genetics.

[4]  A. Sica,et al.  The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[5]  R. Muise-Helmericks,et al.  Signal transduction and the Ets family of transcription factors , 2000, Oncogene.

[6]  M. Colonna,et al.  Phospholipase C-γ2 Is a Critical Signaling Mediator for Murine NK Cell Activating Receptors1 , 2005, The Journal of Immunology.

[7]  D. Cantrell,et al.  Sustained IL-12 Signaling Is Required for Th1 Development 1 , 2004, The Journal of Immunology.

[8]  J. Harty,et al.  CD8+ T cell effector mechanisms in resistance to infection. , 2000, Annual review of immunology.

[9]  C. Tato,et al.  Inhibition of NF-κB Activity in T and NK Cells Results in Defective Effector Cell Expansion and Production of IFN-γ Required for Resistance to Toxoplasma gondii1 , 2003, The Journal of Immunology.

[10]  Christine A. Biron,et al.  Interferon α/β-mediated inhibition and promotion of interferon γ: STAT1 resolves a paradox , 2000, Nature Immunology.

[11]  T. Mak,et al.  WSX-1 is required for the initiation of Th1 responses and resistance to L. major infection. , 2001, Immunity.

[12]  M. Sporn,et al.  Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[13]  R. D. Hatton,et al.  A distal conserved sequence element controls Ifng gene expression by T cells and NK cells. , 2006, Immunity.

[14]  K. Calame,et al.  Ig/EBP-1: a ubiquitously expressed immunoglobulin enhancer binding protein that is similar to C/EBP and heterodimerizes with C/EBP. , 1990, Genes & development.

[15]  J. Ye,et al.  The nuclear factor YY1 suppresses the human gamma interferon promoter through two mechanisms: inhibition of AP1 binding and activation of a silencer element , 1996, Molecular and cellular biology.

[16]  L. Chodosh,et al.  Hlx is induced by and genetically interacts with T-bet to promote heritable TH1 gene induction , 2002, Nature Immunology.

[17]  D. Foster,et al.  IL-21 in Synergy with IL-15 or IL-18 Enhances IFN-γ Production in Human NK and T Cells1 , 2003, The Journal of Immunology.

[18]  A. Bowie,et al.  Ras, Protein Kinase Cζ, and IκB Kinases 1 and 2 Are Downstream Effectors of CD44 During the Activation of NF-κB by Hyaluronic Acid Fragments in T-24 Carcinoma Cells1 , 2000, The Journal of Immunology.

[19]  E. Wherry,et al.  Cutting Edge: IL-12 Inversely Regulates T-bet and Eomesodermin Expression during Pathogen-Induced CD8+ T Cell Differentiation1 , 2006, The Journal of Immunology.

[20]  Hiroshi Sato,et al.  CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. , 1997, Science.

[21]  Heather M. Wilcox,et al.  Signaling through Itk promotes T helper 2 differentiation via negative regulation of T-bet. , 2004, Immunity.

[22]  F. Macian,et al.  NFAT proteins: key regulators of T-cell development and function , 2005, Nature Reviews Immunology.

[23]  D. Schatz,et al.  Up-Regulation of Hlx in Immature Th Cells Induces IFN-γ Expression1 , 2004, The Journal of Immunology.

[24]  Lin Chen,et al.  Transcriptional regulation by calcium, calcineurin, and NFAT. , 2003, Genes & development.

[25]  R. Zinkernagel,et al.  IL-12 is not required for induction of type 1 cytokine responses in viral infections. , 1999, Journal of immunology.

[26]  G. Besra,et al.  A Subset of Liver NK T Cells Is Activated during Leishmania donovani Infection by CD1d-bound Lipophosphoglycan , 2004, The Journal of experimental medicine.

[27]  M. Boothby,et al.  Preferential role for NF-kappa B/Rel signaling in the type 1 but not type 2 T cell-dependent immune response in vivo. , 1999, Journal of immunology.

[28]  T. Hoey,et al.  Cooperative DNA Binding and Sequence-Selective Recognition Conferred by the STAT Amino-Terminal Domain , 1996, Science.

[29]  N. Nagarajan,et al.  Invariant NKT Cells Amplify the Innate Immune Response to Lipopolysaccharide1 , 2007, The Journal of Immunology.

[30]  Jianfei Yang,et al.  T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells , 2002, Nature Immunology.

[31]  F. D. de Sauvage,et al.  IL-27 regulates IL-12 responsiveness of naïve CD4+ T cells through Stat1-dependent and -independent mechanisms , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[32]  J. Farrar,et al.  Type I interferons and T helper development. , 2000, Immunology today.

[33]  O. Kaminuma,et al.  GATA‐3 suppresses IFN‐γ promoter activity independently of binding to cis‐regulatory elements , 2004 .

[34]  S. Szabo,et al.  Distinct Effects of T-bet in TH1 Lineage Commitment and IFN-γ Production in CD4 and CD8 T Cells , 2002, Science.

[35]  S. Akira,et al.  Cutting edge: generation of IL-18 receptor-deficient mice: evidence for IL-1 receptor-related protein as an essential IL-18 binding receptor. , 1999, Journal of immunology.

[36]  J. Farrar,et al.  Pre-assembly of STAT4 with the human IFN-alpha/beta receptor-2 subunit is mediated by the STAT4 N-domain. , 2007, Molecular immunology.

[37]  G. Köhler,et al.  IL-12 is dispensable for innate and adaptive immunity against low doses of Listeria monocytogenes. , 1999, International immunology.

[38]  G. Van Nest,et al.  Induction of interferon‐γ from natural killer cells by immunostimulatory CpG DNA is mediated through plasmacytoid‐dendritic‐cell‐produced interferon‐α and tumour necrosis factor‐α , 2006, Immunology.

[39]  S. Szabo,et al.  Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4 , 1995, The Journal of experimental medicine.

[40]  C. Schindler,et al.  Murine Stat2 is uncharacteristically divergent. , 1999, Nucleic acids research.

[41]  A. Dent,et al.  Regulation of Th2 Cytokine Expression in NKT Cells: Unconventional Use of Stat6, GATA-3, and NFAT21 , 2006, The Journal of Immunology.

[42]  R. Döffinger,et al.  IL-12 and IFN-gamma in host defense against mycobacteria and salmonella in mice and men. , 1999, Current opinion in immunology.

[43]  S. Reiner,et al.  Helper T cell differentiation, inside and out. , 2001, Current opinion in immunology.

[44]  B Perussia,et al.  Activation and expression of the nuclear factors of activated T cells, NFATp and NFATc, in human natural killer cells: regulation upon CD16 ligand binding , 1995, The Journal of experimental medicine.

[45]  James A. Cuff,et al.  A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells , 2006, Cell.

[46]  P. Valdez,et al.  Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis , 2007, Nature.

[47]  Anjana Rao,et al.  TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes , 2002, Nature Immunology.

[48]  Pamela L. Schwartzberg,et al.  T Helper Cell Fate Specified by Kinase-Mediated Interaction of T-bet with GATA-3 , 2005, Science.

[49]  M. Bevan,et al.  Specific immunity to Listeria monocytogenes in the absence of IFN gamma. , 1995, Immunity.

[50]  K. Murphy,et al.  Identification of cooperative monomeric Brachyury sites conferring T-bet responsiveness to the proximal IFN-gamma promoter. , 2003, International immunology.

[51]  M. Caligiuri,et al.  Responsiveness of Naive CD4 T Cells to Polarizing Cytokine Determines the Ratio of Th1 and Th2 Cell Differentiation1 , 2006, The Journal of Immunology.

[52]  M. Neurath,et al.  Cutting Edge: IL-12 and IL-18 Differentially Regulate the Transcriptional Activity of the Human IFN-γ Promoter in Primary CD4+ T Lymphocytes , 1998, The Journal of Immunology.

[53]  A. Sica,et al.  The c-rel protooncogene product c-Rel but not NF-kappa B binds to the intronic region of the human interferon-gamma gene at a site related to an interferon-stimulable response element. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[54]  A. Weiss,et al.  T cell receptor signalling. , 2001, Journal of cell science.

[55]  J. Darnell,et al.  Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. , 1994, Science.

[56]  J. Weissenbach,et al.  Homology between a 173-kb region from mouse chromosome 10, telomeric to the Ifng locus, and human chromosome 12q15. , 2001, Genomics.

[57]  P. Burkett,et al.  Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. , 2006, Annual review of immunology.

[58]  Harinder Singh,et al.  Gene regulatory networks and the determination of lymphoid cell fates. , 2006, Current opinion in immunology.

[59]  R. Locksley,et al.  T helper cell differentiation: on again, off again. , 2002, Current opinion in immunology.

[60]  R. Salomon,et al.  Critical Role for STAT4 Activation by Type 1 Interferons in the Interferon-γ Response to Viral Infection , 2002, Science.

[61]  M. Bevan,et al.  CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection , 2004, Nature Immunology.

[62]  A. Sher,et al.  Mutation of Tec family kinases alters T helper cell differentiation , 2001, Nature Immunology.

[63]  F. Wong,et al.  IFN-γ Affects Homing of Diabetogenic T Cells1 , 2001, The Journal of Immunology.

[64]  Qingsheng Li,et al.  IL-12-Programmed Long-Term CD8+ T Cell Responses Require STAT41 , 2006, The Journal of Immunology.

[65]  L. Hennighausen,et al.  Genetic evidence supporting selection of the Valpha14i NKT cell lineage from double-positive thymocyte precursors. , 2005, Immunity.

[66]  C. Hunter,et al.  Identification of STAT4-Dependent and Independent Mechanisms of Resistance to Toxoplasma gondii1 , 2000, The Journal of Immunology.

[67]  L. Glimcher,et al.  Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development. , 1998, Immunity.

[68]  Suneet Agarwal,et al.  Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. , 1998, Immunity.

[69]  Valeria Poli,et al.  The Role of C/EBP Isoforms in the Control of Inflammatory and Native Immunity Functions* , 1998, The Journal of Biological Chemistry.

[70]  K. Murphy,et al.  Lineage-specific Requirement for Signal Transducer and Activator of  Transcription (Stat)4 in Interferon γ Production from CD4+ Versus CD8+ T Cells , 1999, The Journal of experimental medicine.

[71]  Eric Vivier,et al.  Natural Killer Cell Signaling Pathways , 2004, Science.

[72]  J Wagner,et al.  Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. , 2000, Immunity.

[73]  M. Baron,et al.  An overview of the Notch signalling pathway. , 2003, Seminars in cell & developmental biology.

[74]  T. Aune,et al.  Long-range histone acetylation of the Ifng gene is an essential feature of T cell differentiation. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[75]  J. Lohr,et al.  Regulatory T cells in the periphery , 2006, Immunological reviews.

[76]  J. Farrar,et al.  Recruitment of Stat4 to the Human Interferon-α/β Receptor Requires Activated Stat2* , 2000, The Journal of Biological Chemistry.

[77]  Richard A Flavell,et al.  Transforming growth factor-beta regulation of immune responses. , 2006, Annual review of immunology.

[78]  P. Scott,et al.  IL-12 Is Required to Maintain a Th1 Response During Leishmania major Infection1 , 2000, The Journal of Immunology.

[79]  E. Wherry,et al.  Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin , 2005, Nature Immunology.

[80]  T. Mcclanahan,et al.  IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. , 2002, Immunity.

[81]  F. Alt,et al.  Increased T-cell apoptosis and terminal B-cell differentiation induced by inactivation of the Ets-1 proto-oncogene , 1995, Nature.

[82]  C. Galanos,et al.  Cutting Edge: A Murine, IL-12-Independent Pathway of IFN-γ Induction by Gram-Negative Bacteria Based on STAT4 Activation by Type I IFN and IL-18 Signaling1 , 2002, The Journal of Immunology.

[83]  C. Tato,et al.  Cutting Edge: Innate Production of IFN-γ by NK Cells Is Independent of Epigenetic Modification of the IFN-γ Promoter1 , 2004, The Journal of Immunology.

[84]  Chen Dong,et al.  STAT3 Regulates Cytokine-mediated Generation of Inflammatory Helper T Cells* , 2007, Journal of Biological Chemistry.

[85]  L. Atherly,et al.  The Tec family tyrosine kinases Itk and Rlk regulate the development of conventional CD8+ T cells. , 2006, Immunity.

[86]  K. Asadullah,et al.  IL-22 increases the innate immunity of tissues. , 2004, Immunity.

[87]  W. Ouyang,et al.  The Ets transcription factor ERM is Th1-specific and induced by IL-12 through a Stat4-dependent pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[88]  S. Szabo,et al.  Antigen-driven effector CD8 T cell function regulated by T-bet , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[89]  Jack T. Lin,et al.  TGF-β1 Uses Distinct Mechanisms to Inhibit IFN-γ Expression in CD4+ T Cells at Priming and at Recall: Differential Involvement of Stat4 and T-bet1 , 2005, The Journal of Immunology.

[90]  M. de Carli,et al.  IL-4 and IFN (alpha and gamma) exert opposite regulatory effects on the development of cytolytic potential by Th1 or Th2 human T cell clones. , 1992, Journal of immunology.

[91]  M. Kronenberg,et al.  NKT cells derive from double-positive thymocytes that are positively selected by CD1d , 2001, Nature Immunology.

[92]  K. Murphy,et al.  Th17: an effector CD4 T cell lineage with regulatory T cell ties. , 2006, Immunity.

[93]  Bogdan Tanasa,et al.  Regulation of Th2 differentiation and Il4 locus accessibility. , 2006, Annual review of immunology.

[94]  L. Lefrançois,et al.  Cutting Edge: Requirement for IL-15 in the Generation of Primary and Memory Antigen-Specific CD8 T Cells1 , 2002, The Journal of Immunology.

[95]  R. Flavell,et al.  T helper cell differentiation: regulation by cis elements and epigenetics. , 2006, Immunity.

[96]  R. Rees,et al.  Activation of STAT4 by IL-12 and IFN-alpha: evidence for the involvement of ligand-induced tyrosine and serine phosphorylation. , 1996, Journal of immunology.

[97]  J. Leiden,et al.  Transcriptional regulation of T lymphocyte development and function. , 1999, Annual review of immunology.

[98]  Christine A. Biron,et al.  Coordinated and Distinct Roles for IFN-αβ, IL-12, and IL-15 Regulation of NK Cell Responses to Viral Infection1 , 2002, The Journal of Immunology.

[99]  Yuko Takeba,et al.  Txk, a Member of Nonreceptor Tyrosine Kinase of Tec Family, Acts as a Th1 Cell-Specific Transcription Factor and Regulates IFN-γ Gene Transcription1 , 2002, The Journal of Immunology.

[100]  J. Forman,et al.  Relative Contributions of NK and CD8 T Cells to IFN-γ Mediated Innate Immune Protection against Listeria monocytogenes1 , 2005, The Journal of Immunology.

[101]  J. Ritz,et al.  IL-2 induces STAT4 activation in primary NK cells and NK cell lines, but not in T cells. , 1999, Journal of immunology.

[102]  Christopher A Hunter,et al.  THE ROLE OF CYTOKINES AND THEIR SIGNALING PATHWAYS IN THE REGULATION OF IMMUNITY TO Toxoplasma gondii , 2002, International reviews of immunology.

[103]  Anjana Rao,et al.  Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells , 2007, Nature Immunology.

[104]  J. Casanova,et al.  Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. , 1998, Science.

[105]  K. Murphy,et al.  Issues in T‐helper 1 development – resolved and unresolved , 2004, Immunological reviews.

[106]  J. Curtsinger,et al.  Cutting Edge: Type I IFNs Provide a Third Signal to CD8 T Cells to Stimulate Clonal Expansion and Differentiation1 , 2005, The Journal of Immunology.

[107]  L. Minter,et al.  Notch signalling during peripheral T-cell activation and differentiation , 2007, Nature Reviews Immunology.

[108]  R. Proia,et al.  Lysosomal Glycosphingolipid Recognition by NKT Cells , 2004, Science.

[109]  J. Sprent,et al.  T cell memory. , 2003, Annual review of immunology.

[110]  J. Farrar,et al.  IL-12, but Not IFN-α, Promotes STAT4 Activation and Th1 Development in Murine CD4+ T Cells Expressing a Chimeric Murine/Human Stat2 Gene1 , 2005, The Journal of Immunology.

[111]  C. Hunter,et al.  Type I interferons enhance production of IFN-γ by NK cells , 1997 .

[112]  L. Glimcher,et al.  Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice. , 1996, Immunity.

[113]  H. Nagafuchi,et al.  Txk, a Nonreceptor Tyrosine Kinase of the Tec Family, Is Expressed in T Helper Type 1 Cells and Regulates Interferon γ Production in Human T Lymphocytes , 1999, The Journal of experimental medicine.

[114]  H. Eisen,et al.  Functional differences between memory and naive CD8 T cells. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[115]  Mitchell Kronenberg,et al.  Toward an understanding of NKT cell biology: progress and paradoxes. , 2005, Annual review of immunology.

[116]  S. Bischoff Role of mast cells in allergic and non-allergic immune responses: comparison of human and murine data , 2007, Nature Reviews Immunology.

[117]  Hao Shen,et al.  Control of Effector CD8+ T Cell Function by the Transcription Factor Eomesodermin , 2003, Science.

[118]  T. Aune,et al.  Histone hyperacetylated domains across the Ifng gene region in natural killer cells and T cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[119]  R. Schwartz,et al.  A Distinct Region of the Murine IFN-γ Promoter Is Hypomethylated from Early T Cell Development through Mature Naive and Th1 Cell Differentiation, but Is Hypermethylated in Th2 Cells , 2004, The Journal of Immunology.

[120]  T. Mak,et al.  Interferon regulatory factor-1 is required for a T helper 1 immune response in vivo. , 1997, Immunity.

[121]  M. Biffi,et al.  Selective Expression of an Interleukin-12 Receptor Component by Human T Helper 1 Cells , 1997, Journal of Experimental Medicine.

[122]  Seong-Jin Kim,et al.  Disruption of T Cell Homeostasis in Mice Expressing a T Cell–Specific Dominant Negative Transforming Growth Factor β II Receptor , 2000, The Journal of experimental medicine.

[123]  David E. Levy,et al.  Distinct Requirements for IFNs and STAT1 in NK Cell Function1 , 2000, The Journal of Immunology.

[124]  G. Bouma,et al.  The immunological and genetic basis of inflammatory bowel disease , 2003, Nature Reviews Immunology.

[125]  Kenneth M. Murphy,et al.  Decision making in the immune system: The lineage decisions of helper T cells , 2002, Nature Reviews Immunology.

[126]  M. Boothby,et al.  Opposing Roles for RelB and Bcl-3 in Regulation of T-Box Expressed in T Cells, GATA-3, and Th Effector Differentiation 1 , 2005, The Journal of Immunology.

[127]  T. Decker,et al.  The Yin and Yang of type I interferon activity in bacterial infection , 2005, Nature Reviews Immunology.

[128]  S. Holland,et al.  Defects in the interferon‐γ and interleukin‐12 pathways , 2005, Immunological reviews.

[129]  C. Hunter,et al.  The NF-kappa B family member RelB is required for innate and adaptive immunity to Toxoplasma gondii. , 1999, Journal of immunology.

[130]  J. Casanova,et al.  Genetic dissection of immunity to mycobacteria: the human model. , 2002, Annual review of immunology.

[131]  P. Farnham,et al.  T-bet regulates the terminal maturation and homeostasis of NK and Valpha14i NKT cells. , 2004, Immunity.

[132]  R. Kastelein,et al.  IL-27 and IFN-α Signal via Stat1 and Stat3 and Induce T-Bet and IL-12Rβ2 in Naive T Cells , 2003 .

[133]  J. D. Di Santo,et al.  Roles for Common Cytokine Receptor γ-Chain-Dependent Cytokines in the Generation, Differentiation, and Maturation of NK Cell Precursors and Peripheral NK Cells in Vivo1 , 2005, The Journal of Immunology.

[134]  Lloyd J. Old,et al.  The roles of IFNγ in protection against tumor development and cancer immunoediting , 2002 .

[135]  P. Burkett,et al.  Interleukin (IL)-15Rα–deficient Natural Killer Cells Survive in Normal but Not IL-15Rα–deficient Mice , 2003, The Journal of experimental medicine.

[136]  F. Colucci,et al.  Anatomy of a murder--signal transduction pathways leading to activation of natural killer cells. , 2005, Immunology letters.

[137]  E. Riley,et al.  Whatever turns you on: accessory-cell-dependent activation of NK cells by pathogens , 2007, Nature Reviews Immunology.

[138]  J. Farrar,et al.  Distinct Characteristics of Murine STAT4 Activation in Response to IL-12 and IFN-α1 , 2006, The Journal of Immunology.

[139]  K. Murphy,et al.  Roles of IFN-gamma and IFN-alpha in IL-12-induced T helper cell-1 development. , 1996, Journal of immunology.

[140]  H. Varmus,et al.  Requirement for Tec kinases Rlk and Itk in T cell receptor signaling and immunity. , 1999, Science.

[141]  A. Rao,et al.  Down-regulation of IL-4 gene transcription and control of Th2 cell differentiation by a mechanism involving NFAT1. , 1997, Immunity.

[142]  Richard A Flavell,et al.  Instruction of Distinct CD4 T Helper Cell Fates by Different Notch Ligands on Antigen-Presenting Cells , 2004, Cell.

[143]  M. Biffi,et al.  References Subscriptions Permissions Email Alerts The Role of Stat4 in Species-Specific Regulation of Th Cell Development by Type I , 2013 .

[144]  F.J. Sauvage,et al.  Development of Th1-type immune responses requires the type I cytokine receptor TCCR , 2000, Nature.

[145]  M. Merkenschlager,et al.  Chromatin structure and gene regulation in T cell development and function. , 2006, Current opinion in immunology.

[146]  L. Fouser,et al.  Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides , 2006, The Journal of experimental medicine.

[147]  M. Kurokawa,et al.  Th1‐dominant shift of T cell cytokine production, and subsequent reduction of serum immunoglobulin E response by administration in vivo of plasmid expressing Txk/Rlk, a member of Tec family tyrosine kinases, in a mouse model , 2004, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[148]  R. Schreiber,et al.  Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice , 1998 .

[149]  Fuping Zhang,et al.  T Cell-Intrinsic Requirement for NF-κB Induction in Postdifferentiation IFN-γ Production and Clonal Expansion in a Th1 Response1 , 2003, The Journal of Immunology.

[150]  M. Kronenberg,et al.  The unconventional lifestyle of NKT cells , 2002, Nature Reviews Immunology.

[151]  Peter Fraser,et al.  Remote control of gene transcription. , 2005, Human molecular genetics.

[152]  R. Flavell,et al.  Abrogation of TGFβ Signaling in T Cells Leads to Spontaneous T Cell Differentiation and Autoimmune Disease , 2000 .

[153]  R. Sun,et al.  IL-6 Prevents T Cell-Mediated Hepatitis via Inhibition of NKT Cells in CD4+ T Cell- and STAT3-Dependent Manners , 2004, The Journal of Immunology.

[154]  M. Kubo,et al.  The Runx1 Transcription Factor Inhibits the Differentiation of Naive CD4+ T Cells into the Th2 Lineage by Repressing GATA3 Expression , 2003, The Journal of experimental medicine.

[155]  P. Ohashi,et al.  Differential Roles of Interleukin 15 mRNA Isoforms Generated by Alternative Splicing in Immune Responses in Vivo , 2000, The Journal of experimental medicine.

[156]  M. Wolfe,et al.  Notch Signaling Augments T Cell Responsiveness by Enhancing CD25 Expression 1 , 2003, The Journal of Immunology.

[157]  R. Flavell,et al.  Cutting Edge: Changes in Histone Acetylation at the IL-4 and IFN-γ Loci Accompany Th1/Th2 Differentiation , 2002, The Journal of Immunology.

[158]  Fuping Zhang,et al.  T helper type 1–specific Brg1 recruitment and remodeling of nucleosomes positioned at the IFN-γ promoter are Stat4 dependent , 2006, The Journal of experimental medicine.

[159]  J. Renauld,et al.  IL-TIF/IL-22: genomic organization and mapping of the human and mouse genes , 2000, Genes and Immunity.

[160]  J. Ritz,et al.  Interleukin-2 enhances the response of natural killer cells to interleukin-12 through up-regulation of the interleukin-12 receptor and STAT4. , 2000, Blood.

[161]  I. Puzanov,et al.  IL-15 can substitute for the marrow microenvironment in the differentiation of natural killer cells. , 1996, Journal of immunology.

[162]  L. Gapin,et al.  Developmental program of mouse Vα14i NKT cells , 2005 .

[163]  Graham M Lord,et al.  Recent developments in the transcriptional regulation of cytolytic effector cells , 2004, Nature Reviews Immunology.

[164]  M. Groudine,et al.  Controlling the double helix , 2003, Nature.

[165]  W. Paul,et al.  Interferon γ Stabilizes the T Helper Cell Type 1 Phenotype , 2001, The Journal of experimental medicine.

[166]  N. Muthusamy,et al.  Defective activation and survival of T cells lacking the Ets-1 transcription factor , 1995, Nature.

[167]  J. Casanova,et al.  Inborn errors of IL-12/23- and IFN-γ-mediated immunity: molecular, cellular, and clinical features , 2006 .

[168]  F. Sutterwala,et al.  Transforming growth factor-β controls T helper type 1 cell development through regulation of natural killer cell interferon-γ , 2005, Nature Immunology.

[169]  D. G. Zisoulis,et al.  Stat3 and Stat4 Direct Development of IL-17-Secreting Th Cells1 , 2007, The Journal of Immunology.

[170]  C. Tato,et al.  Opposing roles of NF-κB family members in the regulation of NK cell proliferation and production of IFN-γ , 2006 .

[171]  M J May,et al.  NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. , 1998, Annual review of immunology.

[172]  T. Kouzarides Chromatin Modifications and Their Function , 2007, Cell.

[173]  Anjana Rao,et al.  NFAT1 and NFAT2 are positive regulators of IL‐4 gene transcription , 2002, European journal of immunology.

[174]  G. Blobel,et al.  Histone H3 lysine 9 methylation and HP1gamma are associated with transcription elongation through mammalian chromatin. , 2005, Molecular cell.

[175]  Christine Zimmermann,et al.  Kinetics of the response of naive and memory CD8 T cells to antigen: similarities and differences , 1999, European journal of immunology.

[176]  Laurie H Glimcher,et al.  A Novel Transcription Factor, T-bet, Directs Th1 Lineage Commitment , 2000, Cell.

[177]  C. Croce,et al.  A potential role for interleukin-15 in the regulation of human natural killer cell survival. , 1997, The Journal of clinical investigation.

[178]  U. Boehm,et al.  Cellular responses to interferon-gamma. , 1997, Annual review of immunology.

[179]  M. Caligiuri,et al.  In vivo evidence for a dependence on interleukin 15 for survival of natural killer cells. , 2002, Blood.

[180]  S. Targan,et al.  Enhancer Role of STAT5 in CD2 Activation of IFN-γ Gene Expression1 , 2004, The Journal of Immunology.

[181]  W. M. Weaver,et al.  The Roles of Nuclear Factor of Activated T Cells and Ying-Yang 1 in Activation-induced Expression of the Interferon-γ Promoter in T Cells* , 1998, The Journal of Biological Chemistry.

[182]  W. M. Weaver,et al.  Two essential regulatory elements in the human interferon gamma promoter confer activation specific expression in T cells , 1993, The Journal of experimental medicine.

[183]  The Transcription Factor T-bet Regulates Mucosal T Cell Activation in Experimental Colitis and Crohn's Disease , 2002, The Journal of Experimental Medicine.

[184]  T. Aune,et al.  T-bet antagonizes mSin3a recruitment and transactivates a fully methylated IFN-gamma promoter via a conserved T-box half-site. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[185]  S. Kaufmann,et al.  Mycobacterial phosphatidylinositol mannoside is a natural antigen for CD1d-restricted T cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[186]  R. Savan,et al.  An unexpected discovery of two interferon gamma-like genes along with interleukin (IL)-22 and -26 from teleost: IL-22 and -26 genes have been described for the first time outside mammals. , 2006, Molecular immunology.

[187]  M. Su,et al.  Interferon‐γ expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway , 1998, The EMBO journal.

[188]  G. Trinchieri,et al.  The Reciprocal Interaction of NK Cells with Plasmacytoid or Myeloid Dendritic Cells Profoundly Affects Innate Resistance Functions1 , 2005, The Journal of Immunology.

[189]  D. Rajagopal,et al.  Role of IL-12-Independent and IL-12-Dependent Pathways in Regulating Generation of the IFN-γ Component of T Cell Responses to Salmonella typhimurium1 , 2002, Journal of Immunology.

[190]  A. Sica,et al.  Interaction of NF-κB and NFAT with the Interferon-γ Promoter* , 1997, The Journal of Biological Chemistry.

[191]  Yuka Kanno,et al.  T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription , 2006, The Journal of experimental medicine.

[192]  L. Berg Signalling through TEC kinases regulates conventional versus innate CD8+ T-cell development , 2007, Nature Reviews Immunology.

[193]  R. Flavell,et al.  Transforming Growth Factor-β Controls Development, Homeostasis, and Tolerance of T Cells by Regulatory T Cell-Dependent and -Independent Mechanisms , 2006 .

[194]  Jianfei Yang,et al.  Selective Requirement of p38α MAPK in Cytokine-Dependent, but Not Antigen Receptor-Dependent, Th1 Responses1 , 2006, The Journal of Immunology.

[195]  M. Tsuji,et al.  Superior Protection against Malaria and Melanoma Metastases by a C-glycoside Analogue of the Natural Killer T Cell Ligand α-Galactosylceramide , 2003, The Journal of experimental medicine.

[196]  T. Golde,et al.  Inhibitors of γ-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21 , 2005, Nature Immunology.

[197]  Roberto A. Maldonado,et al.  A role for the immunological synapse in lineage commitment of CD4 lymphocytes , 2004, Nature.

[198]  S. Szabo,et al.  Molecular mechanisms regulating Th1 immune responses. , 2003, Annual review of immunology.

[199]  Michael O Dorschner,et al.  Comprehensive epigenetic profiling identifies multiple distal regulatory elements directing transcription of the gene encoding interferon-γ , 2007, Nature Immunology.

[200]  L. Gapin,et al.  T-bet concomitantly controls migration, survival, and effector functions during the development of Valpha14i NKT cells. , 2006, Blood.

[201]  W. Ouyang,et al.  Unexpected Characteristics of the IFN-γ Reporters in Nontransformed T Cells1 , 2001, The Journal of Immunology.

[202]  D. Levy,et al.  Stat Protein Transactivation Domains Recruit p300/CBP through Widely Divergent Sequences* , 1999, The Journal of Biological Chemistry.

[203]  P. Schwartzberg,et al.  Altered development of CD8+ T cell lineages in mice deficient for the Tec kinases Itk and Rlk. , 2006, Immunity.

[204]  M. Slifka,et al.  Activation of Virus-Specific CD8+ T Cells by Lipopolysaccharide-Induced IL-12 and IL-181 , 2004, The Journal of Immunology.

[205]  Anjana Rao,et al.  Bioinformatics for the 'bench biologist': how to find regulatory regions in genomic DNA , 2004, Nature Immunology.

[206]  P. Hogan,et al.  Transcription factors of the NFAT family: regulation and function. , 1997, Annual review of immunology.

[207]  R. Brutkiewicz CD1d Ligands: The Good, the Bad, and the Ugly1 , 2006, The Journal of Immunology.

[208]  C. Hunter New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions , 2005, Nature Reviews Immunology.

[209]  J. Farrar,et al.  Frontline: Absence of functional STAT4 activation despite detectable tyrosine phosphorylation induced by murine IFN‐α , 2004, European journal of immunology.

[210]  T. Yamamura,et al.  The clinical implication and molecular mechanism of preferential IL-4 production by modified glycolipid-stimulated NKT cells. , 2004, The Journal of clinical investigation.

[211]  T. Huang,et al.  T-bet Binding to Newly Identified Target Gene Promoters Is Cell Type-independent but Results in Variable Context-dependent Functional Effects*♦ , 2006, Journal of Biological Chemistry.

[212]  A. Rao,et al.  A Distal Enhancer in the Interferon-γ (IFN-γ) Locus Revealed by Genome Sequence Comparison* , 2003, Journal of Biological Chemistry.

[213]  G. Trinchieri,et al.  The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. , 2003, Immunity.

[214]  M. Kurimoto,et al.  IFN‐α  and IL‐18 synergistically enhance IFN‐γ  production in human NK cells: differential regulation of Stat4 activation and IFN‐γ  gene expression by IFN‐α  and IL‐12 , 2001 .

[215]  T. Aune,et al.  Cutting Edge: Distal Regulatory Elements Are Required to Achieve Selective Expression of IFN-γ in Th1/Tc1 Effector Cells1 , 2002, The Journal of Immunology.

[216]  N. Clipstone,et al.  Sustained NFAT Signaling Promotes a Th1-Like Pattern of Gene Expression in Primary Murine CD4+ T Cells1 , 2002, The Journal of Immunology.

[217]  M. Caligiuri,et al.  Pro- and antiinflammatory cytokine signaling: reciprocal antagonism regulates interferon-gamma production by human natural killer cells. , 2006, Immunity.

[218]  M. Zasloff,et al.  The nervous system and innate immunity: the neuropeptide connection. , 2005, Nature immunology.

[219]  Bali Pulendran,et al.  Translating Innate Immunity into Immunological Memory: Implications for Vaccine Development , 2006, Cell.

[220]  T. Taniguchi,et al.  Functional dissection of the cytoplasmic subregions of the IL‐2 receptor βc chain in primary lymphocyte populations , 1998, The EMBO journal.

[221]  P. Doherty,et al.  Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells , 1996, Nature.

[222]  Mitchell Kronenberg,et al.  Constitutive Cytokine mRNAs Mark Natural Killer (NK) and NK T Cells Poised for Rapid Effector Function , 2003, The Journal of experimental medicine.

[223]  M Kurimoto,et al.  Influenza A virus-induced IFN-alpha/beta and IL-18 synergistically enhance IFN-gamma gene expression in human T cells. , 1998, Journal of immunology.

[224]  A. Diefenbach,et al.  Dendritic cells prime natural killer cells by trans-presenting interleukin 15. , 2007, Immunity.

[225]  I. Puzanov,et al.  Natural killer cell differentiation: insights from knockout and transgenic mouse models and in vitro systems , 1998, Immunological reviews.

[226]  W. M. Weaver,et al.  Evolutionarily conserved sequence elements that positively regulate IFN-γ expression in T cells , 2004 .

[227]  W. M. Weaver,et al.  The Proximal Regulatory Element of the Interferon-γ Promoter Mediates Selective Expression in T Cells* , 1996, The Journal of Biological Chemistry.

[228]  G. Stark,et al.  Selective loss of type I interferon-induced STAT4 activation caused by a minisatellite insertion in mouse Stat2 , 2000, Nature Immunology.

[229]  N. Sarvetnick,et al.  Cytokines: promoters and dampeners of autoimmunity. , 2002, Current opinion in immunology.

[230]  A. Sher,et al.  T-bet is rapidly induced by interferon-γ in lymphoid and myeloid cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[231]  S. Skurkovich,et al.  Anti-interferon-gamma antibodies in the treatment of autoimmune diseases. , 2003, Current opinion in molecular therapeutics.

[232]  S. Dorman,et al.  Interleukin (IL)-12 and IL-23 are key cytokines for immunity against Salmonella in humans. , 2004, The Journal of infectious diseases.

[233]  J. Massagué TGF-beta signal transduction. , 1998, Annual review of biochemistry.

[234]  F. Berberich-Siebelt,et al.  C/EBPβ enhances IL‐4 but impairs IL‐2 and IFN‐γ induction in T cells , 2000 .

[235]  S. Akira,et al.  Impairment of Natural Killer Cytotoxic Activity and Interferon γ Production in Ccaat/Enhancer Binding Protein γ–Deficient Mice , 1999, The Journal of experimental medicine.

[236]  C. Clendenin,et al.  Defective thymocyte proliferation and IL-2 production in transgenic mice expressing a dominant-negative form of CREB , 1996, Nature.

[237]  A. Sher,et al.  Cutting Edge: IL-12 Is Required for the Maintenance of IFN-γ Production in T Cells Mediating Chronic Resistance to the Intracellular Pathogen, Toxoplasma gondii , 2000, The Journal of Immunology.

[238]  Yong‐jun Liu,et al.  glucocorticoid-induced tumor necrosis factor receptor-ligand (GITRL) Human plasmacytoid predendritic cells activate NK cells through , 2008 .

[239]  T. Walunas,et al.  Cutting Edge: The Ets1 Transcription Factor Is Required for the Development of NK T Cells in Mice1 , 2000, The Journal of Immunology.

[240]  I. Ho,et al.  Ets-1, a functional cofactor of T-bet, is essential for Th1 inflammatory responses , 2005, The Journal of experimental medicine.

[241]  G. Proetzel,et al.  Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease , 1992, Nature.

[242]  R. Seder,et al.  Dealing from the evolutionary pawnshop: how lymphocytes make decisions. , 1999, Immunity.

[243]  J. Forman,et al.  Memory CD8+ T Cells Provide Innate Immune Protection against Listeria monocytogenes in the Absence of Cognate Antigen , 2003, The Journal of experimental medicine.

[244]  C. Dong Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells , 2006, Nature Reviews Immunology.

[245]  T. Aune,et al.  Dynamic changes in histone-methylation 'marks' across the locus encoding interferon-γ during the differentiation of T helper type 2 cells , 2007, Nature Immunology.

[246]  C. Hunter,et al.  STAT1 Plays a Critical Role in the Regulation of Antimicrobial Effector Mechanisms, but Not in the Development of Th1-Type Responses during Toxoplasmosis1 , 2004, The Journal of Immunology.

[247]  M. Tsai,et al.  Effector and potential immunoregulatory roles of mast cells in IgE-associated acquired immune responses. , 2006, Current opinion in immunology.

[248]  N Muthusamy,et al.  The Ets-1 transcription factor is required for the development of natural killer cells in mice. , 1998, Immunity.

[249]  J. Turkson,et al.  STAT3 Activation by Type I Interferons Is Dependent on Specific Tyrosines Located in the Cytoplasmic Domain of Interferon Receptor Chain 2c , 2002, The Journal of Biological Chemistry.

[250]  M. Bachmann,et al.  Distinct kinetics of cytokine production and cytolysis in effector and memory T cells after viral infection , 1999, European journal of immunology.

[251]  R. Flavell,et al.  Interchromosomal associations between alternatively expressed loci , 2005, Nature.

[252]  W. Ouyang,et al.  Signaling and transcription in T helper development. , 2000, Annual review of immunology.

[253]  S. Targan,et al.  A Distal Region in the Interferon-γ Gene Is a Site of Epigenetic Remodeling and Transcriptional Regulation by Interleukin-2* , 2004, Journal of Biological Chemistry.

[254]  A. Bradley,et al.  Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. , 1993, Science.

[255]  Andrew L. Kung,et al.  Role of T-bet in Commitment of TH1 Cells Before IL-12-Dependent Selection , 2001, Science.

[256]  E. Fikrig,et al.  Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1. , 2000, Immunity.

[257]  T. Golde,et al.  TCR-Mediated Notch Signaling Regulates Proliferation and IFN-γ Production in Peripheral T Cells 1 , 2003, The Journal of Immunology.

[258]  A. Rao,et al.  An epigenetic view of helper T cell differentiation , 2003, Nature Immunology.

[259]  G. Trinchieri,et al.  Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes , 1989, Journal of Experimental Medicine.

[260]  A. Krensky,et al.  Human NKT Cells Express Granulysin and Exhibit Antimycobacterial Activity 1 , 2003, The Journal of Immunology.

[261]  R. Smeltz Profound Enhancement of the IL-12/IL-18 Pathway of IFN-γ Secretion in Human CD8+ Memory T Cell Subsets via IL-151 , 2007, The Journal of Immunology.

[262]  M. Fraga,et al.  The Polycomb group protein EZH2 directly controls DNA methylation , 2006, Nature.

[263]  B. Haagmans,et al.  Mice lacking IL-12 develop polarized Th1 cells during viral infection. , 1998, Journal of immunology.

[264]  F. Weih,et al.  Differential Requirement for Rel/Nuclear Factor κB Family Members in Natural Killer T Cell Development , 2003, The Journal of experimental medicine.

[265]  M. Kaplan,et al.  Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice , 1996, Nature.

[266]  R. Locksley,et al.  Mouse Vα14i natural killer T cells are resistant to cytokine polarization in vivo , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[267]  Chen Dong,et al.  MAP kinases in the immune response. , 2002, Annual review of immunology.

[268]  A. Rudensky,et al.  Regulatory T cell lineage specification by the forkhead transcription factor foxp3. , 2005, Immunity.

[269]  M. Colonna,et al.  The Cytotoxicity Receptor CRACC (CS-1) Recruits EAT-2 and Activates the PI3K and Phospholipase Cγ Signaling Pathways in Human NK Cells1 , 2005, The Journal of Immunology.

[270]  P. Rohrlich,et al.  Tmevpg1, a Candidate Gene for the Control of Theiler's Virus Persistence, Could Be Implicated in the Regulation of Gamma Interferon , 2003, Journal of Virology.

[271]  M. Kubo,et al.  Stat5a Inhibits IL-12-Induced Th1 Cell Differentiation through the Induction of Suppressor of Cytokine Signaling 3 Expression1 , 2005, The Journal of Immunology.

[272]  G. Boivin,et al.  Onset and progression of pathological lesions in transforming growth factor-beta 1-deficient mice. , 1995, The American journal of pathology.

[273]  Lewis L Lanier,et al.  NK cell recognition. , 2005, Annual review of immunology.

[274]  R. Zinkernagel,et al.  Immune response in mice that lack the interferon-gamma receptor. , 1993, Science.

[275]  S. Sakaguchi Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self , 2005, Nature Immunology.

[276]  M. Bevan,et al.  Developing and maintaining protective CD8+ memory T cells , 2006, Immunological reviews.

[277]  C. Heusser,et al.  Interferon alpha increases the frequency of interferon gamma-producing human CD4+ T cells , 1993, The Journal of experimental medicine.

[278]  IFN-α and IL-12 Induce IL-18 Receptor Gene Expression in Human NK and T Cells1 , 2000, The Journal of Immunology.

[279]  Pamela L. Schwartzberg,et al.  TEC-family kinases: regulators of T-helper-cell differentiation , 2005, Nature Reviews Immunology.