Advertisement

Checkpoints in the Regulation of T Helper 1 Responses

  • V. L. Heath
  • H. Kurata
  • H. J. Lee
  • N. Arai
  • A. O’Garra
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 266)

Abstract

The immune system has developed to be highly specialized and effective in eradicating a wide variety of pathogens with a minimum of immunopathology. The adaptive arm of the immune response, consisting of antigen-specific T and B cells, interacts with cells of the innate immune system to mediate an effective response to infectious pathogens. Heterogeneity of T cell responses to pathogens can determine the resistance or susceptibility to such infectious agents. In this regard, at least two subsets of CD4+ T helper subsets have been identified; these subsets are characterized by the cytokines they produce and play distinct roles in fighting infection as well as contributing to immunopathology (Mosmann et al. 1986; Romagnani 1991; Sher and Coffman 1992; Abbas 1996). T helper (Th)1 cells produce interferon (IFN)-γ and lymphotoxin and play a critical role in cell-mediated immunity (Mosmann et al. 1986; Sher and Coffman 1992). These cells have also been implicated as being involved in organ-specific autoimmune diseases, such as multiple sclerosis and insulin-dependent diabetes, as well as chronic inflammatory diseases including inflammatory bowel disease (Powrie and Coffman 1993; Liblau et al. 1995; O’Garra 1998). Th2 cells produce interleukin (IL)-4, IL-5, IL-10, and IL-13 and are important in helminth immunity, as well as playing a role in allergy and atopy (Romagnani 1994; O’Garra 1998). Gaining an understanding of the molecular mechanisms of Th1 and Th2 development is critical both for the development of more powerful anti-microbial agents as well as for the development of therapies for immunopathologies.

Keywords

Flow Cytometric Cell Sorting ofTh2 Cell DNAX Research Institute 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abbas AK, Murphy KM, Sher A (1996) Functional diversity of helper T lymphocytes. Nature 383: 787–793PubMedCrossRefGoogle Scholar
  2. Ahn HJ, Maruo S, Tomura M, Mu J, Hamaoka T, Nakanishi K, Clark S, Kurimoto M, Okamura H, Fujiwara H (1997) A mechanism underlying synergy between IL-12 and IFN-y-inducing factor in enhanced production of IFN-y. J Immunol 159: 2125–2131PubMedGoogle Scholar
  3. Bacon CM, Petricoin EF 3rd, Ortaldo JR, Rees RC, Lamer AC, Johnston JA, O’Shea JJ (1995) Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes. Proc Natl Acad Sci USA 92: 7307–7311PubMedCrossRefGoogle Scholar
  4. Bazan JF, Timans JC, Kastelein RA (1996) A newly defined interleukin-1? Nature 379: 591PubMedCrossRefGoogle Scholar
  5. Bohn E, Sing A, Zumbihl R, Bielfeldt C, Okamura H, Kurimoto M, Heesemann JGoogle Scholar
  6. Autenrieth IB (1998) IL-18 (IFN-y-inducing factor) regulates early cytokine production in, and promotes resolution of, bacterial infection in mice. J Immunol 160: 299–307PubMedGoogle Scholar
  7. Born TL, Thomassen E, Bird TA, Sims JE (1998) Cloning of a novel receptor subunit, AcPL, required for interleukin-18 signaling. J Biol Chem 273: 29445–29450PubMedCrossRefGoogle Scholar
  8. Debets R, Timans JC, Churakowa T, Zurawski S, de Waal Malefyt R, Moore KW, Abrams JS, O’Garra A, Bazan JF, Kastelein RA (2000) IL-18 receptors, their role in ligand binding and function: anti-IL-1RAcPL antibody, a potent antagonist of IL-18. J Immunol 165: 4950–4956PubMedGoogle Scholar
  9. Dybing JK, Walters N, Pascual DW (1999) Role of endogenous interleukin-18 in resolving wild-type and attenuated Salmonella typhimurium infections. Infect Immun 67: 6242–6248PubMedGoogle Scholar
  10. Ferber IA, Lee HJ, Zonin F, Heath V, Mui A, Arai N, O’Garra A (1999) GATA-3 significantly downregulates IFN-y production from developing Th1 cells in addition to inducing IL-4 and IL-5 levels. Clin Immunol 91: 134–144PubMedCrossRefGoogle Scholar
  11. Gery I, Lepe-Zuniga JL (1983) Interleukin 1. Lymphokines 9: 109–126Google Scholar
  12. Greenbaum LA, Horowitz JB, Woods A, Pasqualini T, Reich E, Bottomly K (1988) Autocrine growth of CD4+ T cells. Differential effects of IL-1 on helper and inflammatory T cells. J Immunol 140: 1555PubMedGoogle Scholar
  13. Greenfeder SA, Nunes P, Kwee L, Labow M, Chizzonite RA, Ju G (1995) Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex. J Biol Chem 270: 13757–13765PubMedCrossRefGoogle Scholar
  14. Heath VL, Showe L, Crain C, Barrat FJ, Trinchieri G, O’Garra A (2000) Cutting Edge: Ectopic expression of the IL-12-Receptor-132 in developing and committed Th2 cells does not affect the production of IL-4 or induce the production of IFN-y. J Immunol 164: 2861–2865PubMedGoogle Scholar
  15. Hilkens CM, Messer G, Tesselaar K, van Rietschoten AG, Kapsenberg ML, Wierenga EA (1996) Lack of IL-12 signaling in human allergen-specific Th2 cells. J Immunol 157: 4316–4321PubMedGoogle Scholar
  16. Ho IC, 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: 1859–1866Google Scholar
  17. Ho I-C, Hodge MR, Rooney JW, Glimcher LH (1996) The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4. Cell 85: 973–983PubMedCrossRefGoogle Scholar
  18. Ho IC, Vorhees P, Marin N, Oakley BK, Tsai SF, Orkin SH, Leiden JM (1991) Human GATA-3: a lineage-restricted transcription factor that regulates the expression of the T cell receptor alpha gene. Embo J 10: 1187–1192PubMedGoogle Scholar
  19. Hoshino K, Tsutsui H, Kawai T, Takeda K, Nakanishi K, Takeda Y, Akira S (1999) Cutting edge: generation of IL-18 receptor-deficient mice: evidence for IL-1 receptor-related protein as an essential IL-18 binding receptor. J Immunol 162: 5041–5044PubMedGoogle Scholar
  20. Hsieh C-S, Macatonia SE, Tripp CS, Wolf SF, O’Garra A, Murphy KM (1993) Development of Thl CD4+ T cells through IL-12 Produced by Listeria-induced macrophages. Science 260: 547–549PubMedCrossRefGoogle Scholar
  21. Huang H, Paul WE (1998) Impaired interleukin 4 signaling in T helper type 1 cells. J Exp Med 187: 1305–1313PubMedCrossRefGoogle Scholar
  22. Hunter CA, Timans J, Pisacane P, Menon S, Cai G, Chizzonitte R, Bazan JF, Kastelein RA (1997) Comparison of the effects of interleukin-la Interleukin-113 and Interferon-7 inducing factor on the production of interferon-7 by natural killer cells. Eur J Immunol 27: 2787–2792PubMedCrossRefGoogle Scholar
  23. Jacobson NG, Szabo SJ, Weber-Nordt RM, Zhong Z, Schreiber RD, Darnell JEJ, Murphy KM (1995) Interleukin 12 signalling in T helper type 1 (Thl) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (stat)3 and Stat4. J Exp Med 181: 1755–1762PubMedCrossRefGoogle Scholar
  24. Kamogawa Y, Minasi L-aE, Carding SR, Bottomly K, Flavell RA (1993) The relationship of IL-4 and IFN-y-producing T cells studied by lineage ablation of IL-4 producing cells. Cell 75: 985–995PubMedCrossRefGoogle Scholar
  25. Kamogawa Y, Lee HJ, Johnston JA, McMahon M, O’Garra A, Arai N (1998) A conditionally active form of STAT6 can mimic certain effects of 1L-4. J Immunol 161: 10741077Google Scholar
  26. Kaplan M, Schindler U, Smiley ST, Grusby MJ (1996) Stat6 is required for mediating responses to IL-4 and for the development of Th2 cells. Immunity 4: 313–319PubMedCrossRefGoogle Scholar
  27. Kubo M, Ransom J, Webb D, Hashimoto Y, Tada T, Nakayama T (1997) T-cell subset-specific expression of the IL-4 gene is regulated by a silencer element and STAT6. Embo J 16: 4007–4020PubMedCrossRefGoogle Scholar
  28. Kuhn R, Rajewsky K, Muller W (1991) Generation and analysis of interleukin-4 deficient mice. Science 254: 707–710PubMedCrossRefGoogle Scholar
  29. Kurata H, Lee HJ, O’Garra A, Arai N (1999) Ectopic expression of activated Stat6 induces the expression of Th2-specific cytokines and transcription factors in developing Thl cells. Immunity 11: 677–688PubMedCrossRefGoogle Scholar
  30. Lee HJ, O’Garra A, Arai K, Arai N (1998) Characterization of cis-regulatory elements and nuclear factors conferring Th2-specific expression of the IL-5 gene: a role for a GATAbinding protein. J Immunol 160: 2343–2352PubMedGoogle Scholar
  31. Liblau R, Singer S, McDevitt H (1995) Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today 16: 34–38PubMedCrossRefGoogle Scholar
  32. Lichtman AH, Chin J, Schmidt JA, Abbas AK (1988) Role of interleukin 1 in the activation of T lymphocytes. Proc Natl Acad Sci USA 85: 9699–9703PubMedCrossRefGoogle Scholar
  33. Magram J, Connaughton SE, Warrier RR, Carvajal DM, Wu C, Ferrante J, Stewart C, Sarmiento U, Faherty DA, Gately MK (1996) IL-12-deficient mice are defective in IFN-g production and type 1 cytokine responses. Immunity 4: 471–481PubMedCrossRefGoogle Scholar
  34. Manetti R, Parronchi P, Guidizi MG, Piccinni M-P, Maggi E, Trinchieri G, Romagnani S (1993) Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing cells. J Exp Med 177: 1199–1204PubMedCrossRefGoogle Scholar
  35. Mastroeni P, Clare S, Khan S, Harrison JA, Hormaeche CE, Okamura H, Kurimoto M, Dougan G (1999) Interleukin 18 contributes to host resistance and gamma interferon production in mice infected with virulent Salmonella typhimurium. Infect Immun 67: 478–483PubMedGoogle Scholar
  36. McArthur JG, Raulet DH (1993) CD28-induced costimulation of T helper type 2 cells mediated by induction of responsiveness to interleukin 4. J Exp Med 178: 1645–1653PubMedCrossRefGoogle Scholar
  37. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL (1986) Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136: 2348–2357Google Scholar
  38. Murphy E, Shibuya K, Hosken N, Openshaw P, Maino V, Davis K, Murphy K, O’Garra A (1996) Reversibility of T Helper 1 and T Helper 2 Cytokine Profiles is lost after long-term stimulation. J Exp Med 183: 901–913PubMedCrossRefGoogle Scholar
  39. O’Garra A (1998) Cytokines induce the development of functionally heterogeneous T helper cell susbsets. Immunity 8: 275–283PubMedCrossRefGoogle Scholar
  40. Okamura H, Tsutsul H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe K, Okura T, Mukuda Y, Hattori K, Akita K, Namba M, Tanabe K, Konishi K, Fukuda S, Kurimoto M (1995) Cloning of a new cytokine that induces IFN-y production by T cells. Nature 378: 88–91PubMedCrossRefGoogle Scholar
  41. O’Neill LA, Greene C (1998) Signal transduction pathways activated by the IL-1 receptor family: ancient signaling machinery in mammals insects and plants. J Leukoc Biol 63: 650–657PubMedGoogle Scholar
  42. Ouyang W, Ranganath SH, Weindel K, Bhattacharya D, Murphy TL, Sha WC, Murphy KM (1998) Inhibition of Thl development mediated by GATA-3 through an IL4-independent mechanism. Immunity 9: 745–755PubMedCrossRefGoogle Scholar
  43. Ouyang W, Lohning M, Gao Z, Assenmacher M, Ranganath S, Radbruch A, Murphy KM (2000) Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. Immunity 12: 27–37PubMedCrossRefGoogle Scholar
  44. Parnet P, Garka KE, Bonnert TP, Dower SK, Sims JE (1996) IL-1Rrp is a novel receptor-like molecule similar to the type I interleukin-1 receptor and its homologues T1/ST2 and IL-1R AcP. J Biol Chem 271: 3967–3970PubMedCrossRefGoogle Scholar
  45. Powrie F, Coffman RL (1993) Cytokine regulation of T-cell function: potential for therapeutic intervention. Immunol Today 14: 270–274PubMedCrossRefGoogle Scholar
  46. Presky DH, Yang H, Minetti LJ, Chua AO, Nabavi N, Wu CY, Gately MK, Gubler U (1996) A functional interleukin 12 receptor complex is composed of 2 beta-type cytokine receptor subunits. Proc Natl Acad Sci USA 93: 14002PubMedCrossRefGoogle Scholar
  47. Quelle FW, Shimoda K, Thierfelder W, Fischer C, Kim A, Ruben SM, Cleveland JL, Pierce JH, Keegan AD, Nelms K, Paul WE, Ihle JN (1995) Cloning of murine Stat6 and human Stat6, Stat proteins that are tyrosine phosphorylated in responses to IL-4 and IL-3 but are not required for mitogenesis. Mol Cell Biol 15: 3336–3343PubMedGoogle Scholar
  48. Ranganath S, Ouyang W, Bhattarcharya D, Sha WC, Grupe A, Peitz G, Murphy KM (1998) GATA-3-dependent enhancer activity in IL-4 gene regulation. J Immunol 161: 3822–3826PubMedGoogle Scholar
  49. 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 Thl development, but synergizes with IL-12 for interferon-y production, and activates IRAK and NF-03. Immunity 7: 571–581PubMedCrossRefGoogle Scholar
  50. Rocken M, Muller KM, Saurat J-H, Muller I, Louis JA, Cerottini J-C, Hauser C (1992) Central role for TCR/CD3 ligation in the differentiation of CD4+ T cells toward a Thl or Th2 functional phenotype. J Immunol 148: 47–54PubMedGoogle Scholar
  51. Rogge L, Barberis-Maino L, Biffi M, Passini 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: 825–831PubMedCrossRefGoogle Scholar
  52. Romagnani S (1991) Human TH1 and TH2 subsets: doubt no more. Immunol Today 12: 256–257PubMedCrossRefGoogle Scholar
  53. Romagnani S (1994) Lymphokine production by human T cells in disease states. Ann Rev Immunol 12: 227–257CrossRefGoogle Scholar
  54. Ryan JJ, McReynolds LJ, Keegan A, Wang L-H, Garfein E, Rothman P, Nelms K, Paul WE (1996) Growth and gene expression are predominantly controlled by distinct regions of the human IL-4 receptor. Immunity 4: 123–132PubMedCrossRefGoogle Scholar
  55. Seder RA, Gazzinelli R, Sher A, Paul WE (1993) Interleukin 12 acts directly on CD4 T cells to enhance priming for interferon y production and diminishes interleukin 4 inhibition of such priming. Proc Natl Acad Sci USA 90: 10188–10192PubMedCrossRefGoogle Scholar
  56. Sher A, Coffman RL (1992) Regulation of immunity to parasites by T cells and T cell-derived cytokines. Ann Rev Immunol 10: 385–409CrossRefGoogle Scholar
  57. Shibuya K, Robinson D, Zonin F, Hartley SB, Macatonia SE, Somoza C, Hunter CA, Murphy KM, O’Garra A (1998) IL-1 alpha and TNF-alpha are required for IL-12induced development of Thl cells producing high levels of IFN-gamma in BALB/c but not C57BL/6 mice. J Immunol 160: 1708–1716PubMedGoogle Scholar
  58. Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT, Tripp RA, Chu C, Quelle FW, Nosaka T, Vignali DA Doherty PC, Grosveld G, Paul WE, Ihle JN (1996) Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 380: 630–633PubMedCrossRefGoogle Scholar
  59. Sims JE, March CJ, Cosman D, Widmer MB, MacDonald HR, McMahan CJ, Grubin CE, Wignall JM, Jackson JL, Call SM, et al. (1988) cDNA expression cloning of the IL-1 receptor a member of the immunoglobulin superfamily. Science 241: 585–589Google Scholar
  60. Szabo S, Dighe AS, Gubler U, Murphy KM (1997) Regulation of the interleukin (IL)-12132 Subunit expression in developing T helper 1 (Thl) and Th2 Cells. J Exp Med 185: 817–824PubMedCrossRefGoogle Scholar
  61. Szabo SJ, Jacobson NG, Dighe AS, Gubler U, Murphy KM (1995) Developmental Com- mitment to the Th2 Lineage by Exticntion of IL-12 Signaling. Immunity 2: 665–675PubMedCrossRefGoogle Scholar
  62. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH (2000) A novel transcription factor, T-bet, directs Thl lineage commitment. Cell 655–669Google Scholar
  63. Takeda K, Tsutsui H, Yoshimoto T, Adachi O, Yoshida N, Kishimoto T, Okamura H, Nakanishi K, Akira S (1998) Defective NK cell activity and Thl response in IL-18-deficient mice. Immunity 8: 383–390PubMedCrossRefGoogle Scholar
  64. Tanaka-Kataoka M, Kunikata T, Takayama S, Iwaki K, Ohashi K, Ikeda M, Kurimoto M (1999) In vivo antiviral effect of interleukin 18 in a mouse model of vaccinia virus infection. Cytokine 11: 593–599PubMedCrossRefGoogle Scholar
  65. Thierfelder WE, van Deursen JM, Yamamoto K, Tripp RA, Sarawar SR, Carson RT, Sangster MY, Vignali DA, Doherty PC, Grosveld GC, Ihle JN (1996) Requirement for Stat4 in interleukin-12-mdeiated responses of natural killer and T cells. Nature 382: 171–174PubMedCrossRefGoogle Scholar
  66. Ting CN, Olson MC, Barton KP, Leiden JM (1996) Transcription factor GATA-3 is required for development of the T-cell lineage. Nature 384: 474–478PubMedCrossRefGoogle Scholar
  67. Torigoe K, Ushio S, Okura T, Kobayashi S, Taniai M, Kunikata T, Murakami T, Sanou O, Kojima H, Fujii M, Ohta T, Ikeda M, Ikegami H, Kurimoto M (1997) Purification and characterization of the human interleukin-18 receptor. J Biol Chem 272: 25737–25742PubMedCrossRefGoogle Scholar
  68. Trinchieri G (1995) Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Ann Rev Immunol 13: 251–276CrossRefGoogle Scholar
  69. Wang HY, Paul WE, Keegan AD (1996) IL-4 function can be transferred to the IL-2 receptor by tyrosine containing sequences found in the IL-4 receptor a chain. Immunity 4: 113–121PubMedCrossRefGoogle Scholar
  70. Wei XQ, Leung BP, Niedbala W, Piedrafita D, Feng GJ, Sweet M, Dobbie L, Smith AJ, Liew FY (1999) Altered immune responses and susceptibility to Leishmania major and Staphylococcus aureus infection in IL-18-deficient mice. J Immunol 163: 2821–2828PubMedGoogle Scholar
  71. Wu C, Ferrante J, Gately MK, Magram J (1997a) Characterization of IL-12 receptor beta1 chain (IL-12Rbetal)-deficient mice: IL-12Rbetal is an essential component of the functional mouse IL- 12 receptor. J Immunol 159: 1658–1665PubMedGoogle Scholar
  72. Wu C, Warrier RR, Wang X, Presky DH, Gately MK (1997b) Regulation of interleukin-12 receptor betal chain expression and interleukin-12 binding by human peripheral blood mononuclear cells. Eur J Immunol 27: 147–154PubMedCrossRefGoogle Scholar
  73. 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: 1485–1492PubMedCrossRefGoogle Scholar
  74. Yoshimoto T, Takeda K, Tanaka T, Ohkusu K, Kashiwamura S, Okamura H, Akira S, Nakanishi K (1998) IL-12 up-regulates IL-18 receptor expression on T cells, Thl cells, and B cells: synergism with IL-18 for IFN-y production. J Immunol 161: 3400–3407PubMedGoogle Scholar
  75. Zamorano J, Keegan AD (1998) Regulation of apoptosis by tyrosine-containing domains of IL-4R alpha: Y497 and Y713, but not the STAT6-docking tyrosines, signal protection from apoptosis. J Immunol 161: 859–867PubMedGoogle Scholar
  76. Zhang DH, Yang L, Ray A (1998) Differential responsiveness of the IL-5 and IL-4 genes to transcription factor GATA-3. J Immunol 161: 3817–3821PubMedGoogle Scholar
  77. Zhang DH, Cohn L, Ray P, Bottomly K, Ray A (1997) Transcription factor GATA-3 is differentially expressed in murine Thl and Th2 cells and controls Th2-specific expression of the interleukin-5 gene. J Biol Chem 272: 21597–21603PubMedCrossRefGoogle Scholar
  78. Zheng W, Flavell RA (1997) The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89: 587–596PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2002

Authors and Affiliations

  • V. L. Heath
    • 1
  • H. Kurata
    • 1
  • H. J. Lee
    • 1
  • N. Arai
    • 1
  • A. O’Garra
    • 1
  1. 1.Department of ImmunobiologyDNAX Research InstitutePalo AltoUSA

Personalised recommendations