Immunologic Research

, Volume 28, Issue 3, pp 285–293

The role of activation-induced cell death in the differentiation of T-helper-cell subsets

  • Arthur I. Roberts
  • Satish Devadas
  • Xiaoren Zhang
  • Liying Zhang
  • Achsah Keegan
  • Kristy Greeneltch
  • Jennifer Solomon
  • Lixin Wei
  • Jyoti Das
  • Erwei Sun
  • Catherine Liu
  • Zengrong Yuan
  • Jian-nian Zhou
  • Yufang Shi
Article

Abstract

Activation-induced cell death (AICD) has been demonstrated in T-cell hybridomas, immature thymocytes, and activated mature T cells. However, the molecular mechanisms of AICD and its physiological role in T-helper-cell differentiation remain uncertain. Recently, we have shown that Th1 and Th2 cells have distinct mechanisms of AICD. Our findings suggest that signaling from cytokines initiates the differentiation program, but that the selective action of death effectors determines the fate of differentiating T-helper cells, and thus, the ultimate balance between T-helper subpopulations. Among T cells, activation-induced expression of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is observed exclusively in Th2 clones and primary T-helper cells differentiated under Th2 conditions, while the expression of CD95L (Fas ligand) occurs mainly in Th1 cells. Furthermore, Th1 cells are more susceptible than Th2 cells to apoptosis induced through either TRAIL or CD95L, and radiolabeled Th1 cells can be induced into apoptosis via fratricide by both Th1 and Th2 cells, while Th2 cells are spared. The pan-caspase inhibitor, z-VAD, prevents AICD in Th1 cells, but not Th2 cells, indicating different mechanisms of AICD in each T-helper subtype. Antibody blockade of TRAIL and CD95L significantly boosts interferon-γ (IFN-γ) production in vitro. Also, young mice with mutant CD95 (MRL/MpJ-lpr/lpr) have a stronger Th1 response to ovalbumin immunization than do controls. We conclude that apoptosis mediated by CD95L and TRAIL is critical in the selective removal of differentiating T helper cells.

Key Words

Apoptosis AICD TRAIL Fas T Cell 

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References

  1. 1.
    Sharma K, Wang RX, Zhang LY, Yin DL, Luo XY, Solomon JC, et al.: Death the Fas way: regulation and pathophysiology of CD95 and its ligand. Pharmacol Ther 2000;88:333–347.PubMedCrossRefGoogle Scholar
  2. 2.
    Habibovic S, Hrgovic Z, Bukvic I, Hrgovic I: [Molecular mechanisms in apoptosis]. Med Arh 2000;54:33–40.PubMedGoogle Scholar
  3. 3.
    Zimmermann KC, Bonzon C, Green DR: The machinery of programmed cell death. Pharmacol Ther 2001;92:57–70.PubMedCrossRefGoogle Scholar
  4. 4.
    Duke RC, Ojcius DM, Young JD: Cell suicide in health and disease. Sci Am 1996;275:80–87.PubMedCrossRefGoogle Scholar
  5. 5.
    Reed JC, Tomaselli KJ: Drug discovery opportunities from apoptosis research, Curr Opin Biotechnol 2000; 11:586–592.PubMedCrossRefGoogle Scholar
  6. 6.
    Schmitz I, Kirchhoff S, Krammer PH: Regulation of death receptor-mediated apoptosis pathways. Int J Biochem Cell Biol 2000;32:1123–1136.PubMedCrossRefGoogle Scholar
  7. 7.
    McConkey DJ, Jondal M, Orrenius S: Cellular signaling in thymocyte apoptosis. Semin Immunol 1992;4: 371–377.PubMedGoogle Scholar
  8. 8.
    Green DR, Bissonnette RP, Glynn JM, Shi Y: Activation-induced apoptosis in lymphoid systems. Semin Immunol 1992;4:379–388.PubMedGoogle Scholar
  9. 9.
    Ashwell JD, Lu FW, Vacchio MS: Glucocorticoids in T cell development and function. Annu Rev Immunol 2000;18:309–345.PubMedCrossRefGoogle Scholar
  10. 10.
    Lamhamedi-Cherradi SE, Zheng SJ, Maguschak KA, Peschon J, Chen Y.H.: Defective thymocyte apoptosis and accelerated autoimmune diseases in TRAIL(−/−) mice. Nat Immunol 2003;10:10.Google Scholar
  11. 11.
    Chan KF, Siegel MR, Lenardo JM: Signaling by the TNF receptor superfamily and T cell homeostasis. Immunity 2000;13:419–422.PubMedCrossRefGoogle Scholar
  12. 12.
    Scott DW: Analysis of B cell tolerance in vitro. Adv Immunol 1993;54:393–425.PubMedCrossRefGoogle Scholar
  13. 13.
    Scott DW, Grdina T, Shi Y: T cells commit suicide, but B cells are murdered. J Immunol 1996;156:2352–2356.PubMedGoogle Scholar
  14. 14.
    Green DR, Scott DW: Activation-induced apoptosis in lymphocytes. Curr Opin Immunol 1994;6:476–487.PubMedCrossRefGoogle Scholar
  15. 15.
    Henkart PA, Williams MS, Zacharchuk CM, Sarin A: Do CTL kill target cells by inducing apoptosis? Semin Immunol 1997;135–144.Google Scholar
  16. 16.
    Trapani JA, Sutton VR, Smyth MJ: CTL granules: evolution of vesicles essential for combating virus infections. Immunol Today 1999:20:351–356.PubMedCrossRefGoogle Scholar
  17. 17.
    Shi YF, Bissonnette RP, Parfrey N, Szalay M, Kubo RT, Green DR: In vivo administration of monoclonal antibodies to the CD3 T cell receptor complex induces cell death (apoptosis) in immature thymocytes. J Immunol 1991;146:3340–3346.PubMedGoogle Scholar
  18. 18.
    Shi YF, Sahai BM, Green DR: Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes. Nature 1989;339:625–626.PubMedCrossRefGoogle Scholar
  19. 19.
    Smith CA, Williams GT, Kingston R, Jenkinson EJ, Owen JJ: Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. Nature 1989;337:181–184.PubMedCrossRefGoogle Scholar
  20. 20.
    Jenkinson EJ, Kingston R, Smith CA, Williams GT, Owen JJ: Antigen-induced apoptosis in developing T cells: a mechanism for negative selection of the T cell receptor repertoire. Eur J Immunol 1989;19:2175.PubMedCrossRefGoogle Scholar
  21. 21.
    Murphy KM, Heimberger AB, Loh DY: Induction by antigen of intrathymic apoptosis of CD4+CD8+TCR lo thymocytes in vivo. Science 1990;250:1720–1723.PubMedCrossRefGoogle Scholar
  22. 22.
    Sytwu HK, Liblau RS, McDevitt HO: The roles of Fas/APO-1 (CD95) and TNF in antigen-induced programmed cell death in T cell receptor transgenic mice. Immunity 1996;5:17–30.PubMedCrossRefGoogle Scholar
  23. 23.
    Hamad AR, Schneck JP: Antigen-induced T cell death is regulated by CD4 expression. Int Rev Immunol 2001;20:535–546.PubMedGoogle Scholar
  24. 24.
    Mercep M, Bluestone JA, Noguchi PD, Ashwell JD: Inhibition of transformed T cell growth in vitro by monoclonal antibodies directed against distinct activating molecules. J Immunol 1988;140:324–335.PubMedGoogle Scholar
  25. 25.
    Shi YF, Szalay MG, Paskar L, Sahai BM, Boyer M, Singh B, et al.: Activation-induced cell death in T cell hybridomas is due to apoptosis. Morphologic aspects and DNA fragmentation. J Immunol 1990;144:3326–3333.PubMedGoogle Scholar
  26. 26.
    Boehme SA, Lenardo MJ: Ligand-induced apoptosis of mature T lymphocytes (propriocidal regulation) occurs at distinct stages of the cell cycle. Leukemia 1993; 7 Suppl 2:S45-S49.PubMedGoogle Scholar
  27. 27.
    Lenardo MJ: Interleukin-2 programs mouse alpha beta T lymphocytes forapoptosis. Nature 1991;353:858–861.PubMedCrossRefGoogle Scholar
  28. 28.
    Tough DF, Sprent J: Life span if naive and memory T cells. Stem Cells 1995;13:242–249.PubMedCrossRefGoogle Scholar
  29. 29.
    Sprent J, Tough DF: Lymphocyte life-span and memory. Science 1994;265:1395–1400.PubMedCrossRefGoogle Scholar
  30. 30.
    Levine BL, Bernstein WB, Connors M, Craighead N, Lindsten T, Thompson CB, et al.: Effects of CD28 costimulation on long-term proliferation of CD4+ T cells in the absence of exogenous feeder cells. J Immunol 1997;159:5921–5930.PubMedGoogle Scholar
  31. 31.
    Breitmeyer JB, Oppenheim SO, Daley JF, Levine HB, Schlossman SF: Growth inhibition of human T cells by antibodies recognizing the T cell antigen receptor complex. J Immunol 1987;138:726–731.PubMedGoogle Scholar
  32. 32.
    Nau GJ, Moldwin RL, Lancki DW, Kim DK, Fitch FW: Inhibition of IL 2-driven proliferation of murine T lymphocyte clones by supraoptimal levels of immobilized anti-T cell receptor monoclonal antibody. J Immunol 1987;139:114–122.PubMedGoogle Scholar
  33. 33.
    Webb SR, Li JH, MacNeil I, Marrack P, Sprent J, Wilson DB: T cell receptors for responses to Mls determinants and allo-H-2 determinants appear to be encoded on different chromosomes. J Exp Med 1985;161:269–274.PubMedCrossRefGoogle Scholar
  34. 34.
    Bensussan A, Leca G, Corvaia N, Boumsell L: Selective induction of autocytotoxic activity through the CD3 molecule. Eur J Immunol 1990;20:2615–2619.PubMedCrossRefGoogle Scholar
  35. 35.
    Janssen O, Sanzenbacher R, Kabelitz D: Regulation of activation-induced cell death of mature T-lymphocyte populations. Cell Tissue Res 2000;301:85–99.PubMedCrossRefGoogle Scholar
  36. 36.
    Kabelitz D, Janssen O: Antigen-induced death of T-Lymphocytes. Front Biosci 1997;2:d61–77.PubMedGoogle Scholar
  37. 37.
    Janssen O, Wesselborg S, Kabelitz D: Immunosuppression by OK T3—induction of programmed cell death (apoptosis) as a possible mechanism of action. Transplantation 1992;53:233–234.PubMedGoogle Scholar
  38. 38.
    Russell JH: Activation-induced death of mature T cells in the regulation of immune responses. Curr Opin Immunol 1995;7:382–388.PubMedCrossRefGoogle Scholar
  39. 39.
    Baumann S, Krueger A, Kirchhoff S. P. Krammer H: Regulation of T cell apoptosis during the immune response. Curr Mol Med 2002;2:257–272.PubMedCrossRefGoogle Scholar
  40. 40.
    Mountz JD, Zhou T, Su X, Cheng J, Pierson M, Bluethmann H, et al.: Autoimmune disease results from multiple interactive defects in apoptosis induction molecules and signaling pathways. Behring Inst Mitt: 1996;200–219.Google Scholar
  41. 41.
    Donjerkovic D, Scott DW: Activation-induced cell death in B lymphocytes. Cell Res 2000; 10:179–192.PubMedCrossRefGoogle Scholar
  42. 42.
    Kishimoto H, Surh CD, Sprent J: A role for Fas in negative selection of thymocytes in vivo. J Exp Med 1998: 187:1427–1438.PubMedCrossRefGoogle Scholar
  43. 43.
    Zhou T, Edwards CK 3rd, Mountz JD: Prevention of age-related T cell apoptosis defect in CD2-fas-transgenic mice. J Exp Med 1995;182:129–137.PubMedCrossRefGoogle Scholar
  44. 44.
    Simon AK, Williams O, Mongkolsapaya J, Jin B, Xu XN, Walczak H, et al.: Tumor necrosis factor-related apoptosis-inducing ligand in T cell development: sensitivity of human thymocytes. Proc Natl Acad Sci USA 2001;98:5158–5163.PubMedCrossRefGoogle Scholar
  45. 45.
    Wang EC, Thern A, Denzel A, Kitson J, Farrow SN, Owen MJ: DR3 regulates negative selection during thymocyte development. Mol Cell Biol 2001:21:3451–3461.PubMedCrossRefGoogle Scholar
  46. 46.
    Tamada K, Ni J, Zhu G, Fiscella M, Teng B, van Deursen JM, et al.: Cutting edge: selective impairment of CD8+ T cell function in mice lacking the TNF superfamily member LIGH T. J Immunol 2002; 168:4832–4835.PubMedGoogle Scholar
  47. 47.
    Bouillet P, Purton JF, Godfrey DI, Zhang LC, Coultas L, Puthalakath H, et al.: BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 2002;415:922–926.PubMedCrossRefGoogle Scholar
  48. 48.
    Van Parijs L, Abbas AK: Role of Fas-mediated cell death in the regulation of immune responses. Curr Opin Immunol 1996;8:355–361.PubMedCrossRefGoogle Scholar
  49. 49.
    Van Parijs L, Ibraghimov A, Abbas AK: The roles of costimulation and Fas in T cell apoptosis and peripheral tolerance. Immunity 1996;4:321–328.PubMedCrossRefGoogle Scholar
  50. 50.
    Rothstein TL, Wang JK, Panka DJ, Foote LC, Wang Z, Stanger B, et al.: Protection against Fas-dependent Th1-mediated apoptosis by antigen receptor engagement in B cells. Nature 1995:374:163–165.PubMedCrossRefGoogle Scholar
  51. 51.
    Brunner T, Mogil RJ, LaFace D, Yoo NJ, Mahboubi A, Echeverri F, et al.: Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 1995;373: 441–444.PubMedCrossRefGoogle Scholar
  52. 52.
    Ju ST, Panka DJ, Cui H, Ettinger R, el-Khatib M, Sherr DH, et al.: Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 1995;373:444–448.PubMedCrossRefGoogle Scholar
  53. 53.
    Ettinger R, Panka DJ, Wang JK, Stanger BZ, Ju ST, Marshak-Rothstein A: Fas ligand-mediated cytotoxicity is directly responsible for apoptosis of normal CD4+ T cells responding to a bacterial superantigen. J Immunol 1995;154:4302–4308.PubMedGoogle Scholar
  54. 54.
    Pawelec G, Sansom D, Rehbein A, Adibzadeh M, Beckman I: Decreased proliferative capacity and increased susceptibility to activation-induced cell death in latepassage human CD4+ TCR2+ cultured T cell clones. Exp Gerontol 1996;31:655–668.PubMedCrossRefGoogle Scholar
  55. 55.
    Orchansky PL, Teh HS: Activation-induced cell death in proliferating T cells is associated with altered tyrosine phosphorylation of TCR/CD3 subunits. J Immunol 1994;153:615–622.PubMedGoogle Scholar
  56. 56.
    Wang R, Ciardelli TL, Russell JH: Partial signaling by cytokines: cytokine regulation of cell cycle and Fas-dependent, activation-induced death in CD4+ subsets. Cell Immunol 1997;182:152–160.PubMedCrossRefGoogle Scholar
  57. 57.
    Boehme SA, Lenardo MJ: Propriocidal apoptosis of mature T lymphocytes occurs at Sphase of the cell cycle. Eur J Immunol 1993;23:1552–1560.PubMedCrossRefGoogle Scholar
  58. 58.
    Wang R, Brunner T, Zhang L, Shi Y: Fungal metabolite FR901228 inhibits c-Myc and Fas ligand expression. Oncogene 1998;17:1503–1508.PubMedCrossRefGoogle Scholar
  59. 59.
    Zhang XR, Zhang LY, Li L, Glimcher LH, Keegan AD, Shi YF: Reciprocal Expression of TRAIL and CD95L in Th1 and Th2 Cells: Role of Apoptosis in T Helper Subset Differentiation. Cell Death and Differentiation 2003;10:201–210.CrossRefGoogle Scholar
  60. 60.
    Oberg HH, Lengl-Janssen B, Kabelitz D, Janssen O: Activation-induced T cell death: resistance or susceptibility correlate with cell surface fas ligand expression and T helper phenotype. Cell Immunol 1997;181: 93–100.PubMedCrossRefGoogle Scholar
  61. 61.
    Ramsdell F, Seaman MS, Miller RE, Picha KS, Kennedy MK, Lynch DH: Differential ability of Th1 and Th2 T cells to express Fas ligand and to undergo activation-induced cell death. Int Immunol 1994;6:1545–1553.PubMedCrossRefGoogle Scholar
  62. 62.
    Kim J, Woods A, Becker-Dunn E, Bottomly K:Distinct functional phenotypes of cloned Ia-restricted helper T cells. J Exp Med 1985;162:188–201.PubMedCrossRefGoogle Scholar
  63. 63.
    Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL: Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986;136: 2348–2357.PubMedGoogle Scholar
  64. 64.
    Murphy KM: T lymphocyte differentiation in the periphery. Curr Opin Immunol 1998;10:226–236.PubMedCrossRefGoogle Scholar
  65. 65.
    Miner KT, Croft M: Generation, persistence, and modulation of Th0 effector cells: role of autoricine IL-4 and IFN-gamma. J Immunol 1998;160:5280–5287.PubMedGoogle Scholar
  66. 66.
    Constant SL, Bottomly K: Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu Rev Immunol 1997;15:297–322.PubMedCrossRefGoogle Scholar
  67. 67.
    Abbas AK, Murphy KM, Sher A: Functional diversity of helper T lymphocytes. Nature 1996;383:787–793.PubMedCrossRefGoogle Scholar
  68. 68.
    Paul WE, Seder RA: Lymphocyte responses and cytokines. Cell 1994;76:241–251.PubMedCrossRefGoogle Scholar
  69. 69.
    Farrar JD, Ouyang W, Lohning M, Assenmacher M, Radbruch A, Kanagawa O, et al.: An instructive component in T helper cell type 2 (Th2) development mediated by GATA-3. J. Exp Med 2001:193:643–650.PubMedCrossRefGoogle Scholar
  70. 70.
    Kamogawa Y, Minasi LA, Carding SR, Bottomly K, Flavell RA: The relationship of IL-4-and IFN gamma-producing T cells studied by lineage ablation of IL-4-producing cells. Cell 1993;75:985–995.PubMedCrossRefGoogle Scholar
  71. 71.
    Naramura M, Kole HK, Hu RJ, Gu H: Altered thymic positive selection and intracellular signals in Cbl-deficient mice. Proc Natl Acad Sci USA 1998;95: 15547–15552.PubMedCrossRefGoogle Scholar
  72. 72.
    Riviere I, Sunshine MJ, Littman D. R: Regulation of IL-4 expression by activation of individualalleles. Immunity 1998;9:217–228.PubMedCrossRefGoogle Scholar
  73. 73.
    Varadhachary AS, Perdow SN, Hu C, Ramanarayanan M, Salgame P: Differential ability of T cell subsets to undergo activation-induced cell death. Proc Natl Acad Sci USA 1997;94:5778–5783.PubMedCrossRefGoogle Scholar
  74. 74.
    Accornero P, Radrizzani M, Delia D, Gerosa F, Kurrle R, Colombo MP: Differential susceptibility to HIV-GP120-sensitized apoptosis in CD4+T-cell clones with different T-helper phenotypes: role of CD95/CD95L interactions. Blood 1997;89:558–569.PubMedGoogle Scholar
  75. 75.
    Watanabe N, Arase H, Kurasawa K, Iwamoto I, Kayagaki N, Yagita H, et al.: Th1 and Th2 subsets equally undergo Fas-dependent and-independent activation-induced cell death. Eur J Immunol 1997;27:1858–1864.PubMedCrossRefGoogle Scholar
  76. 76.
    Zhou T, Mountz JD, Kimberly RP: Immunobiology of tumor necrosis factor receptor superfamily Immunol Res 2002;26:323–336.PubMedCrossRefGoogle Scholar
  77. 77.
    Secchiero P, Gonelli A, Celeghini C, Mirandola P, Guidotti L, Visani G, et al.: Activation of the nitric oxide synthase pathway represents a key component of tumor necrosis factor-related apoptosis-inducing ligand-mediated cytotoxicity on hematologic malignancies. Blood 2001;98:2220–2228.PubMedCrossRefGoogle Scholar
  78. 78.
    Martinez-Lorenzo MJ, Alava MA, Gamen S, Kim KJ, Chuntharapai A, Pineiro A, et al.: Involvement of APO2 ligand/TRAIL in activation-induced death of Jurkat and human peripheral blood T cells. Eur J Immunol 1998;28:2714–2725.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2003

Authors and Affiliations

  • Arthur I. Roberts
    • 1
  • Satish Devadas
    • 1
  • Xiaoren Zhang
    • 1
  • Liying Zhang
    • 1
  • Achsah Keegan
    • 1
  • Kristy Greeneltch
    • 1
  • Jennifer Solomon
    • 1
  • Lixin Wei
    • 1
  • Jyoti Das
    • 1
  • Erwei Sun
    • 1
  • Catherine Liu
    • 1
  • Zengrong Yuan
    • 1
  • Jian-nian Zhou
    • 1
  • Yufang Shi
    • 1
  1. 1.Department of Molecular Genetics, Microbiology and ImmunologyUniversity of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical SchoolPiscataway

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