Decision making in the immune system: The lineage decisions of helper T cells

After encountering antigen, helper T (TH) cells undergo differentiation to effector cells, which can secrete high levels of interferon-γ, interleukin-4 (IL-4), IL-10 and other immunomodulators. How TH cells acquire, and remember, new patterns of gene expression is an area of intensive investigation. The process is remarkably plastic, with cytokines being key regulators. Extrinsic signals seem to be integrated into cell-intrinsic programming, in what is becoming an intriguing story of regulated development. We summarize the latest insights into mechanisms that govern the lineage choices that are made during TH-cell responses to foreign pathogens.

[1]  T. Lints,et al.  Hlx homeo box gene is essential for an inductive tissue interaction that drives expansion of embryonic liver and gut. , 1996, Genes & development.

[2]  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.

[3]  C. Thompson,et al.  Induction of Cytotoxic T Lymphocyte Antigen 4 (Ctla-4) Restricts Clonal Expansion of Helper T Cells , 2001, The Journal of experimental medicine.

[4]  S. Akira,et al.  Defective NK cell activity and Th1 response in IL-18-deficient mice. , 1998, Immunity.

[5]  F. Finkelman,et al.  Stat6 Regulation of In Vivo IL-4 Responses1 , 2000, The Journal of Immunology.

[6]  R. Locksley,et al.  Analysis of type 2 immunity in vivo with a bicistronic IL-4 reporter. , 2001, Immunity.

[7]  G. Trinchieri,et al.  Cutting Edge: Ectopic Expression of the IL-12 Receptor-β2 in Developing and Committed Th2 Cells Does Not Affect the Production of IL-4 or Induce the Production of IFN-γ1 , 2000, The Journal of Immunology.

[8]  A. Bird.  DNA methylation patterns and epigenetic memory. , 2002, Genes & development.

[9]  J. P. Jackson,et al.  Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase , 2002, Nature.

[10]  Frank R. Lin,et al.  Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. , 2002, Molecular cell.

[11]  R. Locksley,et al.  Rapid expansion and IL-4 expression by Leishmania-specific naive helper T cells in vivo. , 2002, Immunity.

[12]  K. Muegge,et al.  Lsh, a member of the SNF2 family, is required for genome-wide methylation. , 2001, Genes & development.

[13]  A. Sharpe,et al.  Negative co-receptors on lymphocytes. , 2002, Current opinion in immunology.

[14]  T. Mcclanahan,et al.  A Receptor for the Heterodimeric Cytokine IL-23 Is Composed of IL-12Rβ1 and a Novel Cytokine Receptor Subunit, IL-23R1 , 2002, The Journal of Immunology.

[15]  W. Miller,et al.  Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. , 2000, Science.

[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]  X. Hua,et al.  Cell cycle controlling the silencing and functioning of mammalian activators , 2001, Current Biology.

[18]  Prabir Ray,et al.  A critical role for NF-κB in Gata3 expression and TH2 differentiation in allergic airway inflammation , 2001, Nature Immunology.

[19]  J. Sedat,et al.  Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. , 2001, Immunity.

[20]  W. M. Weaver,et al.  A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. , 2001, Immunity.

[21]  Richard A Flavell,et al.  The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells , 1997, Cell.

[22]  W. Paul,et al.  Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4- producing cells , 1990, The Journal of experimental medicine.

[23]  Edward M. Rubin,et al.  Deletion of a coordinate regulator of type 2 cytokine expression in mice , 2001, Nature Immunology.

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

[25]  J. D. Engel,et al.  Expression of the transcription factor GATA‐3 is required for the development of the earliest T cell progenitors and correlates with stages of cellular proliferation in the thymus , 1999, European journal of immunology.

[26]  D. Robinson,et al.  Further checkpoints in Th1 development. , 2002, Immunity.

[27]  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.

[28]  Chyung-Ru Wang,et al.  Helper T cell differentiation is controlled by the cell cycle. , 1998, Immunity.

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

[30]  M. Neurath,et al.  Treatment of Allergic Airway Inflammation and Hyperresponsiveness by Antisense-Induced Local Blockade of Gata-3 Expression , 2001, The Journal of experimental medicine.

[31]  Richard A. Flavell,et al.  Mechanism of Transforming Growth Factor β–induced Inhibition of T Helper Type 1 Differentiation , 2002, The Journal of experimental medicine.

[32]  F. Sallusto,et al.  Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells , 2000, Nature Immunology.

[33]  R. Kastelein,et al.  A Critical Role for Interleukin 18 in Primary and Memory Effector Responses to Listeria monocytogenes That Extends Beyond Its Effects on Interferon γ Production , 2001, The Journal of experimental medicine.

[34]  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.

[35]  S. Akira,et al.  Essential role of Stat6 in IL-4 signalling , 1996, Nature.

[36]  A. Rao,et al.  Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo. , 2000, Immunity.

[37]  W. Paul,et al.  Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted State6 gene , 1996, Nature.

[38]  Andreas Radbruch,et al.  Instruction for Cytokine Expression in T Helper Lymphocytes in Relation to Proliferation and Cell Cycle Progression , 1999, The Journal of experimental medicine.

[39]  Booki Min,et al.  Growth factor independent-1 induced by IL-4 regulates Th2 cell proliferation. , 2002, Immunity.

[40]  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.

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

[42]  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.

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

[44]  A. Ray,et al.  Transcription Factor GATA-3 Is Differentially Expressed in Murine Th1 and Th2 Cells and Controls Th2-specific Expression of the Interleukin-5 Gene* , 1997, The Journal of Biological Chemistry.

[45]  K. Arai,et al.  Cutting Edge: The Differential Involvement of the N-Finger of GATA-3 in Chromatin Remodeling and Transactivation During Th2 Development , 2002, The Journal of Immunology.

[46]  Colin A. Johnson,et al.  Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex , 1998, Nature.

[47]  W. Ouyang,et al.  Induction of interferon‐γ production in Th1 CD4+ T cells: evidence for two distinct pathways for promoter activation , 1999 .

[48]  Kenneth M. Murphy,et al.  Functional diversity of helper T lymphocytes , 1996, Nature.

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

[50]  H. Lee,et al.  Ectopic expression of activated Stat6 induces the expression of Th2-specific cytokines and transcription factors in developing Th1 cells. , 1999, Immunity.

[51]  D. H. Zhang,et al.  Differential responsiveness of the IL-5 and IL-4 genes to transcription factor GATA-3. , 1998, Journal of immunology.

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

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

[54]  A Radbruch,et al.  Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. , 2000, Immunity.

[55]  M. Jackson,et al.  Intercellular adhesion molecule-1 inhibits interleukin 4 production by naive T cells. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

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

[57]  V. Soumelis,et al.  Dendritic cell lineage, plasticity and cross-regulation , 2001, Nature Immunology.

[58]  R. Kastelein,et al.  IGIF Does Not Drive Th1 Development but Synergizes with IL-12 for Interferon-γ Production and Activates IRAK and NFκB , 1997 .

[59]  Suneet Agarwal,et al.  Th2 lineage commitment and efficient IL-4 production involves extended demethylation of the IL-4 gene. , 2002, Immunity.

[60]  W. Paul,et al.  Cell Division Is Not a “Clock” Measuring Acquisition of Competence to Produce IFN-γ or IL-4 , 2001, The Journal of Immunology.

[61]  J. Jeddeloh,et al.  Maintenance of genomic methylation requires a SWI2/SNF2-like protein , 1999, Nature Genetics.

[62]  金城 雄樹.  Contribution of IL-18 to Th1 response and host defense against infection by Mycobacterium tuberculosis : a comparative study with IL-12p40 , 2003 .

[63]  M. Kaplan,et al.  Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. , 1996, Immunity.

[64]  I. N. Crispe,et al.  Functional flexibility in T cells: independent regulation of CD4+ T cell proliferation and effector function in vivo. , 2000, Immunity.

[65]  N. Kadowaki,et al.  Reciprocal control of T helper cell and dendritic cell differentiation. , 1999, Science.

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

[67]  T. Mcclanahan,et al.  Friend of GATA Is Expressed in Naive Th Cells and Functions As a Repressor of GATA-3-Mediated Th2 Cell Development1 , 2002, The Journal of Immunology.

[68]  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.

[69]  W. Paul,et al.  The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice , 1992, The Journal of experimental medicine.

[70]  S. Szabo,et al.  Development of Spontaneous Airway Changes Consistent with Human Asthma in Mice Lacking T-bet , 2002, Science.

[71]  R. Kingston,et al.  Mechanisms of transcriptional memory , 2001, Nature Reviews Molecular Cell Biology.

[72]  Anjana Rao,et al.  A 3' enhancer in the IL-4 gene regulates cytokine production by Th2 cells and mast cells. , 2002, Immunity.

[73]  Andreas Radbruch,et al.  An Instructive Component in T Helper Cell Type 2 (Th2) Development Mediated by Gata-3 , 2001, The Journal of experimental medicine.

[74]  C. Hsieh,et al.  Differential regulation of T helper phenotype development by interleukins 4 and 10 in an alpha beta T-cell-receptor transgenic system. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[75]  J. O’Shea,et al.  Activated STAT4 Has an Essential Role in Th1 Differentiation and Proliferation That Is Independent of Its Role in the Maintenance of IL-12Rβ2 Chain Expression and Signaling , 2002, The Journal of Immunology.

[76]  J. Leiden,et al.  Transcription factor GATA-3 is required for development of the T-cell lineage , 1996, Nature.

[77]  W. Paul,et al.  Impaired Interleukin 4 Signaling in T Helper Type 1 Cells , 1998, The Journal of experimental medicine.

[78]  R. Flavell,et al.  Cutting Edge: TGF-β Inhibits Th Type 2 Development Through Inhibition of GATA-3 Expression , 2000, The Journal of Immunology.

[79]  T. Mosmann,et al.  Single IL-2-secreting precursor CD4 T cell can develop into either Th1 or Th2 cytokine secretion phenotype. , 1994, Journal of immunology.

[80]  J. Strouboulis,et al.  Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription , 1998, Nature Genetics.

[81]  P. A. Peterson,et al.  A key role for ICAM-1 in generating effector cells mediating inflammatory responses , 2001, Nature Immunology.

[82]  L. Glimcher,et al.  The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines. , 1999, Immunity.

[83]  A. O’Garra,et al.  Cutting Edge: Chromatin Remodeling at the IL-4/IL-13 Intergenic Regulatory Region for Th2-Specific Cytokine Gene Cluster1 , 2000, The Journal of Immunology.

[84]  Paul Tempst,et al.  MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex , 1999, Nature Genetics.

[85]  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.

[86]  R. Flavell,et al.  Regulation of IL-4 gene expression by distal regulatory elements and GATA-3 at the chromatin level. , 2001, Immunity.

[87]  J. Renauld,et al.  IL-23 and IL-12 Have Overlapping, but Distinct, Effects on Murine Dendritic Cells1 , 2002, The Journal of Immunology.

[88]  I. Ho,et al.  ROG, repressor of GATA, regulates the expression of cytokine genes. , 2000, Immunity.

[89]  L. Glimcher,et al.  NFATc1 and NFATc2 together control both T and B cell activation and differentiation. , 2001, Immunity.

[90]  T. Kitamura,et al.  Regulation of Th2 cell differentiation by mel-18, a mammalian polycomb group gene. , 2001, Immunity.

[91]  A. Weinberg,et al.  IL-4 directs the development of Th2-like helper effectors. , 1990, Journal of immunology.

[92]  G. Peltz,et al.  GATA-3-dependent enhancer activity in IL-4 gene regulation. , 1998, Journal of immunology.

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

[94]  S. Orkin,et al.  Friend of GATA-1 Represses GATA-3–dependent Activity in CD4+ T Cells , 2001, The Journal of experimental medicine.

[95]  L. Glimcher,et al.  c-maf Promotes T Helper Cell Type 2 (Th2) and Attenuates Th1 Differentiation by Both Interleukin 4–dependent and –independent Mechanisms , 1998, The Journal of experimental medicine.

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

[97]  D. H. Zhang,et al.  Inhibition of allergic inflammation in a murine model of asthma by expression of a dominant-negative mutant of GATA-3. , 1999, Immunity.

[98]  R. Flavell,et al.  The relationship of IL-4- and IFNγ-producing T cells studied by lineage ablation of IL-4-producing cells , 1993, Cell.

[99]  A. Sher,et al.  Single Cell Analysis Reveals That IL-4 Receptor/Stat6 Signaling Is Not Required for the In Vivo or In Vitro Development of CD4+ Lymphocytes with a Th2 Cytokine Profile , 2000, The Journal of Immunology.

[100]  J. Bluestone,et al.  LFA-1 interaction with ICAM-1 and ICAM-2 regulates Th2 cytokine production. , 1998, Journal of immunology.

[101]  E. Kieff,et al.  A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes , 1996, Journal of virology.

[102]  W. Ouyang,et al.  Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. , 1998, Immunity.

[103]  S. Elgin,et al.  Epigenetic Codes for Heterochromatin Formation and Silencing Rounding up the Usual Suspects , 2002, Cell.

[104]  R. Coffman,et al.  Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. , 1986, Journal of immunology.

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

[106]  C. Hsieh,et al.  Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. , 1993, Science.

[107]  W. Ouyang,et al.  IL-18–stimulated GADD45β required in cytokine-induced, but not TCR-induced, IFN-γ production , 2001, Nature Immunology.

[108]  C. Hunter,et al.  Bystander Activation of CD8+ T Cells Contributes to the Rapid Production of IFN-γ in Response to Bacterial Pathogens1 , 2001, The Journal of Immunology.

[109]  M. Tomlinson,et al.  TGF‐β1 down‐regulates Th2 development and results in decreased IL‐4‐induced STAT6 activation and GATA‐3 expression , 2000 .

[110]  James Douglas Engel,et al.  Targeted disruption of the GATA3 gene causes severe abnormalities in the nervous system and in fetal liver haematopoiesis , 1995, Nature Genetics.

[111]  C. Allis,et al.  Translating the Histone Code , 2001, Science.

[112]  N. Glaichenhaus,et al.  The role of antigen and IL-12 in sustaining Th1 memory cells in vivo: IL-12 is required to maintain memory/effector Th1 cells sufficient to mediate protection to an infectious parasite challenge. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[113]  H. Lee,et al.  GATA-3 significantly downregulates IFN-gamma production from developing Th1 cells in addition to inducing IL-4 and IL-5 levels. , 1999, Clinical immunology.

[114]  Laurie H Glimcher,et al.  The Proto-Oncogene c-maf Is Responsible for Tissue-Specific Expression of Interleukin-4 , 1996, Cell.

[115]  Naoko Arai,et al.  Gata-3 Induces T Helper Cell Type 2 (Th2) Cytokine Expression and Chromatin Remodeling in Committed Th1 Cells , 2000, The Journal of experimental medicine.

[116]  F. Sallusto,et al.  Two subsets of memory T lymphocytes with distinct homing potentials and effector functions , 1999, Nature.

[117]  A. Bird,et al.  Gene silencing quantitatively controls the function of a developmental trans-activator. , 2002, Molecular cell.