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Educating T cells: early events in the differentiation and commitment of cytokine-producing CD4+ and CD8+ T cells

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Abstract

T lymphocytes acquire the ability to synthesize cytokines during their primary response to antigen, often giving rise to effector populations with a polarized type 1 or type 2 cytokine profile. However, polarization is not a simple choice between two differentiation pathways. This article reviews the evidence, particularly from single-cell and clonal studies, that polarization is the outcome of a series of stochastic events whose probabilities are determined in part by genetic background and in part by extracellular signals received during activation and clonal expansion. The data suggest that these extracellular signals independently and differentially regulate the probability of expression of each cytokine gene, for example by their effects on clonal expansion and chromatin remodeling, CpG demethylation and transcriptional activation of cytokine genes. Polarization is, therefore, achieved at the population level by altering frequencies of expression among cells with many different expression patterns, rather than by selective differentiation of a discrete subset. Type 1 and type 2 populations progressively lose responsiveness to counter-polarizing stimuli. While the molecular basis of this process is not yet known, the observed persistence of cells with flexible cytokine profiles in some polarized populations suggests that loss of flexibility may also be a probabilistic event.

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References

  1. Abbas AK, Murphy KM, Sher A (1996) Functional diversity of helper T lymphocytes. Nature 383:787

    Google Scholar 

  2. Agarwal S, Rao A (1998) Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity 9:765

    Google Scholar 

  3. Assenmacher M, Löhning M, Scheffold A, Manz RA, Schmitz J, Radbruch A (1998) Sequential production of IL-2, IFN-γ and IL-10 by individual staphylococcal enterotoxin B-activated T helper lymphocytes. Eur J Immunol 28:1534

    Google Scholar 

  4. Assenmacher M, Löhning M, Scheffold A, Richter A, Miltenyi S, Schmitz J, Radbruch A (1998) Commitment of individual Th1-like lymphocytes to expression of IFN-γ versus IL-4 and IL- 10:selective induction of IL-10 by sequential stimulation of naive Th cells with IL-12 and IL-4. J Immunol 161:2825

    Google Scholar 

  5. Assenmacher M, Schmitz J, Radbruch A (1994) Flow cytometric determination of cytokines in activated murine T helper lymphocytes: expression of interleukin-10 in interferon-γ and in interleukin-4expressing cells. Eur J Immunol 24:1097

    Google Scholar 

  6. Bendelac A, Rivera MN, Park S-H, Roark JH (1997) Mouse CD1-specific NK1T cells: development, specificity, and function. Annu Rev Immunol 15:535

    Google Scholar 

  7. Bird JJ, Brown DR, Mullen AC, Moskowitz NH, Mahowald MA, Sider JR, Gajewski TF, Wang C-R, Reiner SL (1998) Helper T cell differentiation is controlled by the cell cycle. Immunity 9:229

    Google Scholar 

  8. Bix M, Locksley RM (1998) Independent and epigenetic regulation of the interleukin-4 alleles in CD4+ T cells. Science 281:1352

    Google Scholar 

  9. Bix M, Wang Z-E, Thiel B, Schork NJ, Locksley RM (1998) Genetic regulation of commitment to interleukin 4 production by a CD4+ T cell-intrinsic mechanism. J Exp Med 188:2289

    Google Scholar 

  10. Borish L (1999) Genetics of allergy and asthma. Ann Allergy Asthma Immunol 82:413

    Google Scholar 

  11. Brown KE, Baxter J, Graf D, Merkenschlager M, Fisher AG (1999) Dynamic repositioning of genes in the nucleus of lymphocytes preparing for cell division. Mol Cell 3:207

    Google Scholar 

  12. Buoy RP, Karr L, Huang G, Li J, Carter D, Honjo K, Lemons JA, Murphy KM, Weaver CT (1995) Single cell analysis of cytokine gene coexpression during CD4+ T-cell phenotype development. Proc Natl Acad Sci USA 92:7565

    Google Scholar 

  13. Buoy RP, Panoskaltsis-Mortari A, Huang G, Li J, Karr L, Ross M, Russell JH, Murphy KM, Weaver CT (1994) Heterogeneity of single cell cytokine gene expression in clonal T cell populations. J Exp Med 180:1251

    Google Scholar 

  14. Cai Z, Brunmark AB, Luxembourg AT, Garcia KC, Degano M, Teyton L, Wilson I, Peterson PA, Sprent J, Jackson MR (1998) Probing the activation requirements for naive CD8+ T cells withDrosophila cell transfectants as antigen presenting cells. Immunol Rev 165:249

    Google Scholar 

  15. Cantrell D (1996) T cell antigen receptor signal transduction pathways. Annu Rev Immunol 14:259

    Google Scholar 

  16. Carson DA, Raz E (1997) Oligonucleotide adjuvants for T helper 1 (Th1)-specific vaccination. J Exp Med 186:1621

    Google Scholar 

  17. Carter LL, Murphy KM (1999) Lineage-specific requirement for signal transducer and activator of transcription (Stat)4 in interferon γ production from CD4+ versus CD8+ T cells. J Exp Med 189:1355

    Google Scholar 

  18. Cerwenka A, Carter LL, Reome JB, Swain SL, Dutton RW (1998) In vivo persistence of CD8 polarized T cell subsets producing type 1 or type 2 cytokines. J Immunol 161:97

    Google Scholar 

  19. Chen Y, Kuchroo VK, Inobe J, Haller DA, Weiner HL (1994) Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265:1237

    Google Scholar 

  20. Clark SJ, Harrison J, Paul CL, Frommer M (1994) High sensitivity mapping of methylated cytosines. Nucleic Acids Res 22:2990

    Google Scholar 

  21. Cockerill PN, Shannon MF, Bert AG, Ryan GR, Vadas MA (1993) The granulocyte-macrophage colony-stimulating factor/interleukin 3 locus is regulated by an inducible cyclosporin A-sensitive enhancer. Proc Natl Acad Sci USA 90:2466

    Google Scholar 

  22. Constant SL, Bottomly K (1997) Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu Rev Immunol 51:297

    Google Scholar 

  23. Cosman D (1987) Control of messenger RNA stability. Immunol Today 8:16

    Google Scholar 

  24. Croft M, Carter L, Swain SL, Dutton RW (1994) Generation of polarized antigen-specific CD8 effector populations: reciprocal action of interleukin (IL)-4 and IL-12 in promoting type 2 versus type 1 cytokine profiles. J Exp Med 180:1715

    Google Scholar 

  25. De Smedt T, Van Mechelen M, De Becker G, Urbain J, Leo O, Moser M (1997) Effect of interleukin10 on dendritic cell maturation and function. Eur J Immunol 27:1229

    Google Scholar 

  26. Egerton M, Fitzpatrick DR, Catling AD, Kelso A (1996) Differential activation of T cell cytokine production by the extracellular signal-regulated kinase (ERK) signaling pathway. Eur J Immunol 26:2279

    Google Scholar 

  27. Egerton M, Fitzpatrick DR, Kelso A (1998) Activation of the extracellular signal-regulated kinase pathway is differentially required for TCR-stimulated production of six cytokines in primary T lymphocytes. Int Immunol 10:223

    Google Scholar 

  28. Falchetti R, Di Francesco P, Lanzilli G, Gaziano R, Casalinuovo IA, Palamara AT, Ravagnan G, Garaci E (1998) Determination of cytokine co-expression in individual splenic CD4+ and CD8+ T cells from influenza virus-immune mice. Immunology 95:346

    Google Scholar 

  29. Firestein GS, Roeder WD, Laxer JA, Townsend KS, Weaver CT, Horn JT, Linton J, Torbert BE, Glasebrook AL (1989) A new murine CD4+ T cell subset with an unrestricted cytokine profile. J Immunol 143:518

    Google Scholar 

  30. Fitzpatrick DR, Kelso A (1998) Independent regulation of cytokine genes in T cells: the paradox in the paradigm. Transplantation 65:1

    Google Scholar 

  31. Fitzpatrick DR, Shirley KM, Kelso A (1999) Cutting edge: stable epigenetic inheritance of regional IFN-γ promoter demethylation in CD44high CD8+ T lymphocytes. J Immunol 162:5053

    Google Scholar 

  32. Fitzpatrick DR, Shirley KM, McDonald LE, Bielefeldt-Ohmann H, Kay GF, Kelso A (1998) Distinct methylation of the interferon-γ (IFN-γ ) and interleukin-3 (IL-3) genes in newly activated primary CD8+ T lymphocytes: regional IFN-γ promoter demethylation and mRNA expression are heritable in CD44high CD8+ T cells. J Exp Med 188:103

    Google Scholar 

  33. Freeman GJ, Boussiotis VA, Anumanthan A, Bernstein GM, Ke XY, Rennert PD, Gray GS, Gribben JG, Nadler LM (1995) B7-1 and B7-2 do not deliver identical costimulatory signals, since B7-2 but not B7-1 preferentially costimulates the initial production of IL-4. Immunity 2:523

    Google Scholar 

  34. Gett AV, Hodgkin PD (1998) Cell division regulates the T cell cytokine repertoire, revealing a mechanism underlying immune class regulation. Proc Natl Acad Sci USA 95:9488

    Google Scholar 

  35. Glimcher LH, Singh H (1999) Transcription factors in lymphocyte development — T and B cells get together. Cell 96:13

    Google Scholar 

  36. Gough NM, Kelso A (1989) GM-CSF expression is preferential to multi-CSF (IL-3) expression in murine T lymphocyte clones. Growth Factors 1:287

    Google Scholar 

  37. Groux H, O'Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389:737

    Google Scholar 

  38. Güler ML, Gorham JD, Dietrich WE, Murphy TL, Steen RG, Parvin CA, Fenoglio D, Grupe A, Pelt G, Murphy KM (1999)Tpm1, a locus controlling IL-12 responsiveness, acts by a cell-autonomous mechanism. J Immunol 162:1339

    Google Scholar 

  39. Güler ML, Gorham JD, Hsieh C-S, Mackey AJ, Steen RG, Dietrich WE, Murphy KM (1996) Genetic susceptibility toLeishmania: IL-12 responsiveness in TH1 cell development. Science 271:984

    Google Scholar 

  40. Hardy KJ, Peterlin BM, Atchison RE, Stobo JD (1985) Regulation of expression of the human interferon γ gene. Proc Natl Acad Sci USA 82:8173

    Google Scholar 

  41. Ho I-C, Lo D, Glimcher LH (1998) c-maf promotes T helper cell type 2 (Th2) and attenuates Thl differentiation by both interleukin 4-dependent and -independent mechanisms. J Exp Med 188:1859

    Google Scholar 

  42. Holländer GA, Zuklys S, Morel C, Mizoguchi E, Mobisson K, Simpson S, Terhorst C, Wishart W, Golan DE, Bhan AK, Burakoff SJ (1998) Monoallelic expression of the imerleukin-2 locus. Science 279:2118

    Google Scholar 

  43. Hosken NA, Shibuya K, Heath AW, Murphy KM, O'Garra A (1995) The effect of antigen dose on CD4+ T helper cell phenotype development in a T cell receptor-αβ-transgenic model. J Exp Med 182:1579

    Google Scholar 

  44. Hsieh CS, Macatonia SE, Tripp CS, Wolf SF, O'Garra A, Murphy KM (1993) Development of TH1 CD4+ T cells through IL-12 produced byListeria-induced macrophages. Science 260:547

    Google Scholar 

  45. Hsieh C-S, Heimberger AB, Gold JS, O'Garra A, Murphy KM (1992) Differential regulation of T helper phenotype development by interleukins 4 and 10 in an αβ T-cell-receptor transgenic system. Proc Natl Acad Sci USA 89:6065

    Google Scholar 

  46. Huang H, Paul WE (1998) Impaired interleukin 4 signaling in T helper type 1 cells. J Exp Med 187:1305

    Google Scholar 

  47. Hu-Li J, Huang H, Ryan J, Paul WE (1997) In differentiated CD4+ T cells, interleukin 4 production is cytokine-autonomous, whereas interferon γ production is cytokine-dependent. Proc Natl Acad Sci USA 94:3189

    Google Scholar 

  48. Itoh Y, Germain RN (1997) Single cell analysis reveals regulated hierarchical T cell antigen receptor signaling thresholds and intraclonal heterogeneity for individual cytokine responses of CD4+ T cells. J Exp Med 186:757

    Google Scholar 

  49. Janeway CA, Bottomly K (1994) Signals and signs for lymphocyte responses. Cell 76:275

    Google Scholar 

  50. Kaplan MH, Grusby MJ (1998) Regulation of T helper cell differentiation by STAT molecules. J Leukoc Biol 64:2

    Google Scholar 

  51. Katamura K, Fukui T, Kiyomasu T, Iio J, Tai G, Ueno H, Heike T, Mayumi M, Furushi K (1998) IL-4 and prostaglandin E2 inhibit hypomethylation of the 5′ regulatory region of IFN-γ gene during differentiation of naive CD4+ T cells. Mol Immunol 35:39

    Google Scholar 

  52. Kawamura T, Takeda K, Mendiratta SV, Kawamura H, Van Kaer L, Yagita H, Abo T, Okumura K (1998) Cutting edge: critical role of NK1+ T cells in IL-12-induced immune responses in vivo. J Immunol 160:16

    Google Scholar 

  53. Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, Ueno H, Nakagawa R, Sato H, Kondo E, Koseki H, Taniguchi M (1997) CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides. Science 278:1626

    Google Scholar 

  54. Kelso A (1995) Th1 and Th2 subsets: paradigms lost? Immunol Today 16:374

    Google Scholar 

  55. Kelso A, Gough NM (1988) Coexpression of granulocyte-macrophage colony-stimulating factor, γ interferon, and interleukins 3 and 4 is random in murine alloreactive T-lymphocyte clones. Proc Natl Acad Sci USA 85:9189

    Google Scholar 

  56. Kelso A, Groves P (1997) A single peripheral CD8+ T cell can give rise to progeny expressing type 1 and/or type 2 cytokine genes and can retain its multipotentiality through many cell divisions. Proc Natl Acad Sci USA 94:8070

    Google Scholar 

  57. Kelso A, Groves P, Ramm L, Doyle AG (1999) Single-cell analysis by RT-PCR reveals differential expression of multiple type 1 and 2 cytokine genes among cells within polarized CD4+ T cell populations. Int Immunol 11:617

    Google Scholar 

  58. Kelso A, Groves P, Troutt AB, Francis K (1995) Evidence for the stochastic acquisition of cytokine profile by CD4+ T cells activated in a T helper type 2-like response in vivo. Eur J Immunol 25:1168

    Google Scholar 

  59. Kelso A, Owens T (1988) Production of two hemopoietic growth factors is differentially regulated in single T lymphocytes activated with an anti-T cell receptor antibody. J Immunol 140:1159

    Google Scholar 

  60. Kelso A, Troutt AB, Maraskovsky E, Gough NM, Morris L, Pech MH, Thomson JA (1991) Heterogeneity in lymphokine profiles of CD4+ and CD8+ T cells and clones activated in vivo and in vitro. Immunol Rev 123:85

    Google Scholar 

  61. Kiani A, Viola JPB, Lichtman AH, Rao A (1997) Down-regulation of IL-4 gene transcription and control of Th2 cell differentiation by a mechanism involving NFAT1. Immunity 7:849

    Google Scholar 

  62. Kim J, Sif S, Jones B, Jackson A, Koipally J, HellerE, Winandy S, Viel A, Sawyer A, Ikeda T, Kingston R, Georgopoulos K (1999) Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes. Immunity 10:345

    Google Scholar 

  63. Kirillov A, Kistler B, Mostoslavsky R, Cedar H, Wirth T, Bergman Y (1996) A role for nuclear NF-κB in B-cell-specific demethylation of the Igκ locus. Nat Genet 13:435

    Google Scholar 

  64. Kosarova M, Havelkova H, Krulova M, Demant P, Lipoldova M (1999) The production of two Th2 cytokines, interleukin-4 and interleukin-10, is controlled independently by locus Cypr1 and by loci Cypr2 and Cypr3, respectively. Immunogenetics 49:134

    Google Scholar 

  65. Kuchroo VK, Das MP, Brown JA, Ranger AM, Zamvil SS, Sobel RA, Weiner HL, Nabavi N, Glimcher LH (1995) B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy. Cell 80:707

    Google Scholar 

  66. Lanzavecchia A, Iezzi G, Viola A (1999) From TCR engagement to T cell activation: a kinetic view of T cell behavior. Cell 96:1

    Google Scholar 

  67. Launois P, Maillard I, Pingel S, Swihart KG, Xénarios I, Acha-Orbea H, Diggelmann H, Locksley RM, MacDonald HR, Louis JA (1997) IL-4 rapidly produced by Vβ4 Vα8 CD4+ T cells instructs Th2 development and susceptibility to Leishmania major in BALB/c mice. Immunity 6:541

    Google Scholar 

  68. Le Gros G, Ben-Sasson SZ, Seder R, Finkelman FD, Paul WE (1990) 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. J Exp Med 172:921

    Google Scholar 

  69. Lederer JA, Perez VL, DesRoches L, Kim SM, Abbas AK, Lichtman AH (1996) Cytokine transcriptional events during helper T cell subset differentiation. J Exp Med 184:397

    Google Scholar 

  70. Li B, Tournier C, Davis RJ, Flavell RA (1999) Regulation of IL-4 expression by the transcription factor JunB during T helper cell differentiation. EMBO J 18:420

    Google Scholar 

  71. Lindsten T, June CH, Ledbetter JA, Stella G, Thompson CB (1989) Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway. Science 244:339

    Google Scholar 

  72. Maggi E, Del Prete G, Macchia D, Parronchi P, Tiri A, Chrétien I, Ricci M, Romagnani S (1988) Profiles of lymphokine activities and helper function for IgE in human T cell clones. Eur J Immunol 18:1045

    Google Scholar 

  73. Maldonado-López R, De Smedt T, Michel P, Godfroid J, Pajak B, Heirman C, Thielemans K, Leo O, Urbain J, Moser M (1999) CD8α+ and CD8α-subclasses of dendritic cells direct the development of distinct T helper cells in vivo. J Exp Med 189:587

    Google Scholar 

  74. McAdam AJ, Schweitzer AN, Sharpe AH (1998) The role of B7 costimulation in activation and differentiation of CD4+ and CD8+ T cells. Immunol Rev 165:231

    Google Scholar 

  75. McKenzie GJ, Fallon PG, Emson CL, Grencis RK, McKenzie AN (1999) Simultaneous disruption of interleukin (IL)-4 and IL-13 defines individual roles in T helper cell type 2-mediated responses. J Exp Med 189:1565

    Google Scholar 

  76. Melvin AJ, McGurn ME, Bort SJ, Gibson C, Lewis DB (1995) Hypomethylation of the interferon-γ gene correlates with its expression by primary T-lineage cells. Eur J Immunol 25:426

    Google Scholar 

  77. Mikovits JA, Young HA, Vertino P, Issa JPJ, Pitha PM, Turcoski-Corrales S, Taub DD, Petrow CL, Baylin SB, Ruscetti FW (1998) Infection with human immunodeficiency virus type I upregulates DNA methyltransferase, resulting in de novo methylation of the gamma interferon (IFN-γ) promoter and subsequent downregulation of IFN-γ production. Mol Cell Biol 18:5166

    Google Scholar 

  78. Mocci S, Coffman RL (1997) The mechanism of in vitro T helper cell type 1 to T helper cell type 2 switching in highly polarizedLeishmania major-specific T cell populations. J Immunol 158:1559

    Google Scholar 

  79. Morris L, Troutt AB, Handman E, Kelso A (1992) Changes in the precursor frequencies of IL-4 and IFN-γ secreting CD4+ cells correlate with resolution of lesions in murine cutaneous leishmaniasis. J Immunol 149:2715

    Google Scholar 

  80. Mosmann TR, Coffman RL (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145

    Google Scholar 

  81. Mosmann TR, Sad S (1996) The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 17:138

    Google Scholar 

  82. Murphy E, Shibuya K, Hosken N, Openshaw P, Maino V, Davis K, Murphy K, O'Garra A (1996) Reversibility of T helper 1 and 2 populations is lost after long-term stimulation. J Exp Med 183:901

    Google Scholar 

  83. Murphy KM (1998) T lymphocyte differentiation in the periphery. Curr Opin Immunol 10:226

    Google Scholar 

  84. Nakamura T, Lee RK, Nam SY, Podack ER, Bottomly K, Flavell RA (1997) Roles of IL-4 and IFN-γ in stabilizing the T helper cell type 1 and 2 phenotype. J Immunol 158:2648

    Google Scholar 

  85. Naramura M, Hu R-J, Gu H (1998) Mice with a fluorescent marker for interleukin 2 gene activation. Immunity 9:209

    Google Scholar 

  86. O'Garra A (1998) Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8:275

    Google Scholar 

  87. Ouyang W, Jacobson NG, Bhattacharya D, Gorham JD, Fenoglio D, Sha WC, Murphy TL, Murphy KM (1999) The Ets transcription factor ERM is Th1-specific and induced by IL-12 through a Stat4-dependent pathway. Proc Natl Acad Sci USA 96:3888

    Google Scholar 

  88. Ouyang W, Ranganath SH, Weindel K, Bhattacharya D, Murphy TL, Sha WC, Murphy KM (1998) Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. Immunity 9:745

    Google Scholar 

  89. Paliard X, de Waal Malefijt R, Yssel H, Blanchard D, Chrétien I, Abrams J, de Vries J, Spits H (1988) Simultaneous production of IL-2, IL-4, and IFN-γ by activated human CD4+ and CD8 T cell clones. J Immunol 141:849

    Google Scholar 

  90. Penix LA, Sweetser MT, Weaver WM, Hoeffler JP, Kerppola TK, Wilson CB (1996) The proximal regulatory element of the interferon-γ promoter mediates selective expression in T cells. J Biol Chem 271:31964

    Google Scholar 

  91. Perez VL, Lederer JA, Lichtman AH, Abbas AK (1995) Stability of Th1 and Th2 populations. Int Immunol 7:869

    Google Scholar 

  92. Picker LJ, Singh MK, Zdraveski Z, Treer JR, Wladrop SL, Bergstresser PR, Maino VC (1995) Direct demonstration of cytokine synthesis heterogeneity among human memory/effector T cells by flow cytometry. Blood 86:1408

    Google Scholar 

  93. Powell JD, Ragheb JA, Kitagawa-Sakakida S, Schwartz RH (1998) Molecular regulation of interleukin-2 expression by CD28 co-stimulation and anergy. Immunol Rev 165:287

    Google Scholar 

  94. Pulendran B, Smith JL, Caspary G, Brasel K, Pettit D, Maraskovsky E, Mahszewski CR (1999) Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. Proc Natl Acad Sci USA 96:1036

    Google Scholar 

  95. Ramsdell F, Seaman MS, Miller RE, Picha KS, Kennedy MK, Lynch DH (1994) Differential ability of Th1 and Th2 cells to express Fas ligand and to undergo activation-induced cell death. Int Immunol 6:1545

    Google Scholar 

  96. Rincón M, Enslen H, Raingeaud J, Recht M, Zapton T, Su MS-S, Penix LA, Davis RJ, Flavell RA (1998) Interferon-γ expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway. EMBO J 17:2817

    Google Scholar 

  97. Rissoan M-C, Soumelis V, Kadowaki N, Grouard G, Briere F, de Waal Malefyt R, Liu Y-J (1999) Reciprocal control of T helper cell and dendritic cell differentiation. Science 283:1183

    Google Scholar 

  98. Rivière I, Sunshine MJ, Littman DR (1998) Regulation of IL-4 expression by activation of individual alleles. Immunity 9:217

    Google Scholar 

  99. Robinson D, Shibuya K, Mui A, Zonin F, Murphy E, Sana T, Hartley SB, Menon S, Kastelein R, Bazan F, O'Garra A (1997) IGIF does not drive Th1 development but synergizes with IL-12 for interferon-γ production and activates IRAK and NF-κB. Immunity 7:571

    Google Scholar 

  100. Röcken M, Saurat J-H, Hauser C (1992) A common precursor for CD4+ T cells producing IL-2 or IL4. J Immunol 148:1031

    Google Scholar 

  101. Rogge L, Barberis-Maino L, Biffi M, Passim N, Presky DH, Gubler U, Sinigaglia F (1997) Selective expression of an interleukin-12 receptor component by human T helper 1 cells. J Exp Med 185:825

    Google Scholar 

  102. Ross IL, Browne CM, Hume DA (1994) Transcription of individual genes in eukaryotic cells occurs randomly and infrequently. Immunol Cell Biol 72:177

    Google Scholar 

  103. Rothenberg RV, Ward SB (1996) A dynamic assembly of diverse transcription factors integrates activation and cell-type information for interleukin 2 gene regulation. Proc Natl Acad Sci USA 93:9358

    Google Scholar 

  104. Rulifson IC, Sperling AI, Fields PE, Fitch FW, Bluestone JA (1997) CD28 costimulation promotes the production of Th2 cytokines. J Immunol 158:658

    Google Scholar 

  105. Sad S, Marcotte R, Mosmann TR (1995) Cytokine-induced differentiation of precursor mouse CD8+ T cells into cytotoxie CD8+ T cells secreting Th1 or Th2 cytokines. Immunity 2:271

    Google Scholar 

  106. Sad S, Mosmann TR (1994) Single IL-2-secreting precursor CD4T cell can develop into either Th1 or Th2 cytokine secretion phenotype. J Immunol 153:3514

    Google Scholar 

  107. Seder RA, Boulay J-L, Finkelman F, Barbier S, Ben-Sasson SZ, Le Gros G, Paul WE (1992) CD8+ T cells can be primed in vitro to produce IL-4. J Immunol 148:1652

    Google Scholar 

  108. Seder RA, Paul WE (1994) Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol 12:635

    Google Scholar 

  109. Seder RA, Paul WE, Davis MM, Fazekas de St. Groth B (1992) The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice. J Exp Med 176:1091

    Google Scholar 

  110. Siebenlist U, Durand DB, Bressler P, Holbrook NJ, Norris CA, Kamoun M, Kant JA, Crabtree GR (1986) Promoter region of interleukin-2 gene undergoes chromatin structure changes and confers inducibility on chloramphenicol acetyltransferase gene during activation of T cells. Mol Cell Biol 6:3042

    Google Scholar 

  111. Sommer F, Meixner M, Mannherz M, Ogilvie ALJ, Röllinghoff M, Lohoff M (1998) Analysis of cytokine patterns produced by individual CD4+ lymph node cells during experimental murine leishmaniasis in resistant and susceptible mice. Int Immunol 10:1853

    Google Scholar 

  112. Sornasse T, Larenas PV, Davis KA, de Vries JE, Yssel H (1996) Differentiation and stability of T helper 1 and 2 cells derived from naive human neonatal CD4+ T cells, analyzed at the single-cell level. J Exp Med 184:473

    Google Scholar 

  113. Street NE, Schumacher JH, Fong TAT, Bass H, Fiorentino DF, Leverah JA, Mosmann TR (1990) Heterogeneity of mouse helper T cells. Evidence from bulk cultures and limiting dilution cloning for precursors of Th1 and Th2 cells. J Immunol 144:1629

    Google Scholar 

  114. Swain SL (1994) Generation and in vivo persistence of polarized Th1 and Th2 memory cells. Immunity 1:543

    Google Scholar 

  115. Swain SL, Weinberg AD, English M, Huston G (1990) IL-4 directs the development of Th2-like helper effectors. J Immunol 145:3796

    Google Scholar 

  116. Szabo SJ, Dighe AS, Gubler U, Murphy KM (1997) Regulation of the interleukin (IL)-12R (32 subunit expression in developing T helper 1 (Th1) and Th2 cells. J Exp Med 185:817

    Google Scholar 

  117. Szabo SJ, Jacobson NG, Dighe AS, Gubler U, Murphy KM (1995) Developmental commitment to the Th2 lineage by extinction of IL-12 signaling. Immunity 2:665

    Google Scholar 

  118. Tanaka Y, Nakashima H, Hisano C, Kohsaka T, Nemoto Y, Niiro H, Otsuka T, Otsuka T, Imamura T, Niho Y (1999) Associations of the interferon-γ receptor variant Va114Met) with systemic lupus erythematosus. Immunogenetics 49:266

    Google Scholar 

  119. Trinchieri G (1995) Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol 13:251

    Google Scholar 

  120. Troutt AB, Kelso A (1992) Enumeration of lymphokine mRNA-containing cells in vivo in a murine graft-versus-host reaction using the PCR. Proc Natl Acad Sci USA 89:5276

    Google Scholar 

  121. Valentine JE, Sewell WA (1998) Characterisation of inducible DNase I hypersensitive sites flanking the human interleukin-5 gene. Biochim Biophys Acta 1442:218

    Google Scholar 

  122. Ward SB, Hernandez-Hoyos G, Chen F, Waterman M, Reeves R, Rothenberg EV (1998) Chromatin remodeling of the interleukin-2 gene: distinct alterations in the proximal versus distal enhancer regions. Nucleic Acids Res 26:2923

    Google Scholar 

  123. Weiner HL (1997) Oral tolerance: immune mechanisms and treatment of autoimmune diseases. Immunol Today 18:335

    Google Scholar 

  124. Xu D, Chan WL, Leung BP, Hunter D, Schulz K, Carter RW, McInnes IB, Robinson JH, Liew FY (1998) Selective expression and functions of interleukin 18 receptor on T helper (Th) type 1 but not Th2 cells. J Exp Med 188:1485

    Google Scholar 

  125. Young HA, Ghosh P, Ye J, Lederer J, Lichtman A, Gerard JR, Penix L, Wilson CB, Melvin AJ, McGurn ME, Lewis DB, Taub DD (1994) Differentiation of the T helper phenotypes by analysis of the methylation state of the IFN-γ gene. J Immunol 153:3603

    Google Scholar 

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Kelso, A. Educating T cells: early events in the differentiation and commitment of cytokine-producing CD4+ and CD8+ T cells. Springer Semin Immunopathol 21, 231–248 (1999). https://doi.org/10.1007/BF00812255

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