Bioprobes pp 97-123 | Cite as

Immune Cell Functions

  • Kazuo Nagai
  • Takao Kataoka


The immune response, as expressed in its most sophisticated form in higher vertebrates including humans, is a self defense mechanism that works to protect the host by distinguishing and neutralizing or destroying the non-self substances, such as abnormal cells or invading infectious agents. All cells participating in immune reactions are derived from pluripotent hematopoietic stem cells produced in the bone marrow.The stem cells differentiate into myeloid progenitors and common lymphoid progenitors.The myeloid progenitors are the precursor of the granulocytes and macrophages. There are three types of granulocytes, neutrophils, eosinophils and basophils. The common lymphoid progenitors give rise to the lymphocytes which are divided into two major groups, B lymphocytes and T lymphocytes. These lymphocytes have antigen receptors, the surface immunoglobulin of B cells and the antigen receptor of T cells (TCR). B cells can detect antigen outside the cell, while on the other hand, T cells recognize antigens that are generated inside the cell and expressed on the cell surface as molecules combined with a major histocompatibility complex (MHC).Upon activation, B lymphocytes differentiate into plasma cells, which secrete antibodies. There are two main classes of T lymphocytes, helper T cells (TH), which activate immune cells such as B cells and macrophages, and cytotoxic T lymphocytes (CTLs), which kill virus-infected cells and the cells of transplanted tissues or organs bearing altered MHC-peptides.


Mycophenolic Acid Mixed Lymphocyte Reaction FasL Expression Immune Cell Function Granule Exocytosis 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Morris RE (1993) New small molecule immunosuppressants for transplantation: review of essential concepts. J Heart Lung Transplant 12:S275–286PubMedGoogle Scholar
  2. 2.
    Morris RE (1995) Mechanism of action of new immunosuppressive drugs. The Drug Monit 17:564–569CrossRefGoogle Scholar
  3. 3.
    Halloran PF (1996) Molecular mechanism of new immunosuppressive agents. Clin Transplantation 10:118–123Google Scholar
  4. 4.
    Gerber DA, Bonham CA, Thompson AW (1998) Immunosuppressive agents: Recent developments in molecular action and clinical application. Transplant Proc 30:1573–1579PubMedCrossRefGoogle Scholar
  5. 5.
    Schwartz RS, Stack J, Dameshek W (1958) Effect of 6-mercaptopurine on antibody production. Proc Soc Exp Biol Med 88:164–167Google Scholar
  6. 6.
    Gilblett EL, Anderson JE, Cohen F, Plara B, Neuwissen HJ (1972) Adenosine deaminase deficiency in two patients with severely impaired cellular immunity. Lancet ii:1067–1069CrossRefGoogle Scholar
  7. 7.
    Gilblett EL, Ammann AJ, Wara DW, Sadma R, Diamond LK (1975) Nucleoside phosphorylase deficiency in child with severely defective T-cell immunity and normal B-cell immunity. Lancet i:1010–1011CrossRefGoogle Scholar
  8. 8.
    Georgiev VST (1993) Enzymes of the purine metabolism: Inhibition and therapeutic potential. Ann N Y Acad Sci 685:207–216CrossRefGoogle Scholar
  9. 9.
    Koyama H, Tsuji M (1983) Genetic and biochemical studies on the activation of and cytotoxic mechanism of bredinin, a potent inhibitor of purine biosynthesis in mammalian cells. Biochem Pharmacol 32:3547–3553PubMedCrossRefGoogle Scholar
  10. 10.
    Ichikawa Y, Ihara H, Takahara S, Takada K, Shrestha GR, Ishibashi M, Arima M, Sagawa S, Sonoda T (1984) The immunosuppressive mode of action of mizoribine. Transplantation 38:262–267PubMedCrossRefGoogle Scholar
  11. 11.
    Allison AC, Hovi T, Watts RWE, Webster ADB (1975) Immunological observations on patients with Lesch-Nyhan syndrome, and on the role of de novo purine synthesis in lymphocyte transformation. Lancet ii:1179–1183CrossRefGoogle Scholar
  12. 12.
    Kayama K, Okubo M, Ishigamori E, Masaki Y, Uchida H, Watanabe K, Kashiwagi N (1983) Immunosuppressive effect of bredinin on cell-mediated and humoral immune reactions in experimental animals. Transplantation 35:144–1449CrossRefGoogle Scholar
  13. 13.
    Mitchell BS, Dayton JS, Turka LA, Thompson CB (1993) IMP dehydrogenase inhibitors as immunomodulators. Ann N Y Acad Sci 685:217–224PubMedCrossRefGoogle Scholar
  14. 14.
    Hirohata S, Yanagita T (1995) Inhibition of expression of cyclin A in human B cells by an immunosuppressant mizoribine. J Immunol 155:5175–5183PubMedGoogle Scholar
  15. 15.
    Sweeney MJ, Hoffman DH, Esterman MA (1972) Metabolism and biochemistry of mycophenolic acid. Cancer Res 32:1803–1809PubMedGoogle Scholar
  16. 16.
    Lee WA, Gu L, Miksztal AR, Nancy C, Kwan L, Nelson PH (1990) Bioavailability improvement of mycophenolic acid through amino ester derivatization. Pharm Res 7:161–166PubMedCrossRefGoogle Scholar
  17. 17.
    Franklin TJ, Cook JM (1969) The inhibition of nucleic acid synthesis by mycophenolic acid. Biochem J 113:515–524PubMedGoogle Scholar
  18. 18.
    Natsumeda Y, Ohno S, Kawasaki H, Konno Y, Weber G, Suzuki K (1990) Two distinct cDNAs for human IMP dehydrogenase. J Biol Chem 265:5292–5295PubMedGoogle Scholar
  19. 19.
    Nagai M, Natsumeda Y, Weber G (1992) Proliferation-linked regulation of the type II IMP dehydrogenase gene in human normal lymphocytes and HL-60 leukemic cells. Cancer Res 52:258–261PubMedGoogle Scholar
  20. 20.
    Carr SF, Rapp E, Wu JC, Natsumeda Y (1993) Characterization of human type I and type II IMP dehydrogenases. J Biol Chem 268:27286–27290PubMedGoogle Scholar
  21. 21.
    Allison AC, Eugui EM (1994) Preferential suppression of lymphocyte proliferation by mycophenolic acid and predicted long-term effects of mycophenolate mofetil in transplantation. Transplant Proc 26:3205–3210PubMedGoogle Scholar
  22. 22.
    Allison AC, Eugui EM (1993) The design and development of an immunosuppressive drug, mycophenolate mofetil. Springer Semin Immunopathol 14:353–380PubMedCrossRefGoogle Scholar
  23. 23.
    Makowka L, Sher L, Cramer D (1993) The development of brenquinar as an immunosuppressive drug for transplantation. Immunol Rev 136:51–70PubMedCrossRefGoogle Scholar
  24. 24.
    Ruckemann K, Fairbanks LD, Carrey EA, Hawrylowicz CM, Richards DF, Kirschbaum B, Simmonds HN (1998) Leflunomide inhibits pyrimidine de novo synthesis in mitogenstimulated T-lymphocytes from healthy humans. J Biol Chem 273:21682–21691PubMedCrossRefGoogle Scholar
  25. 25.
    Chong AS, Rezai K, Gebel HM, Finnegan A, Foster P, Xu X, Williams JW (1996) Effects of leflunomide and other immunosuppressive agents on T cell proliferation in vitro. Transplantation 15:140–145CrossRefGoogle Scholar
  26. 26.
    Bader B, Knecht W, Fries M, Loffler M (1998) Expression, purification, and characterization of histidine-tagged rat and human flavoenzyme dehydroorotate dehydrogenase. Protein Expr Purif 13:414–422PubMedCrossRefGoogle Scholar
  27. 27.
    Knecht W, Loffler M (1998) Species-related inhibition of human and rat dihydroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives. Biochem Pharmacol 56:1259–1264PubMedCrossRefGoogle Scholar
  28. 28.
    Xu X, Williams JW, Shen J, Gong H, Yin DP, Blinder L, Elder R, Sankary H, Finegan A, Chong ASF (1998) In vitro and in vivo mechanisms of action of the antiproliferative and immunosuppressive agents, brequinar sodium. J Immunol 160:846–853PubMedGoogle Scholar
  29. 29.
    Xu X, Williams JW, Bremer EG, Gong H, Finnegan A, Chong ASF (1996) Two activities of the immunosuppressive metabolite of leflunomide, A77 1726. Inhibition of pyrimidine nucleotide synthesis and protein tyrosine phosphorylation. Biochem Pharmcol 52:527–534CrossRefGoogle Scholar
  30. 30.
    Siemasko K, Chong ASF, Jack HM, Gong H, Williams JW, Finnegan A (1998) Inhibition of JAK3 and STAT6 tyrosine phosphorylation by the immunosuppressive drug leflunomide leads to a block in IgGI production. J Immunol 160:1581–1588PubMedGoogle Scholar
  31. 31.
    Manna SK, Aggarwal BB (1999) Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-KB activation and gene expression. J Immunol 162:2095–2102PubMedGoogle Scholar
  32. 32.
    Nishizuka Y (1992) Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258:607–614PubMedCrossRefGoogle Scholar
  33. 33.
    Ferris CD, Snyder H (1992) 1,4,5-Triphosphate activated calcium channels. Ann Rev Physiol 54:469–488CrossRefGoogle Scholar
  34. 34.
    Berridge MJ (1995) Capacitative calcium entry. Biochem J 312:1–11PubMedGoogle Scholar
  35. 35.
    Stemmer PM, Klee CB (1994) Dual calcium regulation of calcineurin by calmodulin and calcineurin B. Biochemistry 33:6859–6866PubMedCrossRefGoogle Scholar
  36. 36.
    Shaw KTY, Ho AM, Raghavan A, Kim J, Jain J, Park J, Surendra S, Rao A, Hogan PG (1995) Immunosuppressive drugs prevent a rapid dephosphorylation of transcription factor NFAT1 in stimulated immune cells. Proc Natl Acad Sci USA 92:11205–11209PubMedCrossRefGoogle Scholar
  37. 37.
    Frantz B, Nordby EC, Bren G, Steffan N, Paya CV, Kincaid RL, Tocci MJ, O’Keefe SJ, O’Neill EA (1994) Calcineurin acts in synergy with PMA to inactivate IKB/MAD3, an inhibitor of NF-KB. EMBO J 13:861–870PubMedGoogle Scholar
  38. 38.
    Quesniauz VF (1993) Immunosuppressants: Tools to investigate the physiological role of cytokines. BioEssays 15:731–739CrossRefGoogle Scholar
  39. 39.
    Cai W, Hu L, Foulkes JG (1996) Transcription-modulating drugs: mechanism and selectivity. Curr Opin Biotechnol 7:608–615PubMedCrossRefGoogle Scholar
  40. 40.
    Bram RJ, Hung DT, Martin PK, Schreiber SL, Crabtree GR (1993) Identification of the immunophilins capable of mediating inhibition of signal transduction by cyclosporin and FK506: role of calcineurin binding and cellular location. Mol Cell Biol 13:4760–4769PubMedGoogle Scholar
  41. 41.
    Galat A (1993) Peptidylproline cis-trans-isomerase: immunophilins. Eur J Biochem 216:689–707PubMedCrossRefGoogle Scholar
  42. 42.
    Kissinger CR, Parge HE, Knighton DR, Lewis CT, Pelletier LA, Tempczyk A, Ksalish V, Tucker KD, Showalter RE, Moomaw EW et al. (1995) Crystal structure of human calcineurin and the human FKBP12-calcineurin complex. Nature 378:641–644PubMedCrossRefGoogle Scholar
  43. 43.
    Schreiber SL, Crabtree GR (1992) The mechanism of action of cyclosporin A and FK506. Immunology Today 13:136–142PubMedCrossRefGoogle Scholar
  44. 44.
    Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH (1994) RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78:35–43PubMedCrossRefGoogle Scholar
  45. 45.
    Brown El, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, Schreiber SL (1994) A mammalian protein targeted by G1-arresting rapamycin receptor complex. Nature 369:756–758PubMedCrossRefGoogle Scholar
  46. 46.
    Brown El, Beal PA, Keith CT, Chen J, Shin TB, Schreiber SL (1995) Control of p70 S6 kinase by FRAP in vivo. Nature 377:411–416CrossRefGoogle Scholar
  47. 47.
    Pearson RB, Dennis PB, Han JW, Williamson NA, Kozma SC, Wettenhall REH, Thomas G (1995) The principle target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. EMBO J 21:5279–5287Google Scholar
  48. 48.
    De Groot RP, Ballou LM, Sassonew-Corsi P (1994) Positive regulation of the cAM Presponsive activator CREM by the p70 S6 kinase: and alternative route to mitogeninduced gene expression. Cell 79:81–91PubMedCrossRefGoogle Scholar
  49. 49.
    Jefferies HBJ, Reinhard C, Kozma SC, Thomas G (1994) Rapamycin selectively represses transition of the polypyrimidine tract mRNA family. Proc Natl Acad Sci USA 91:4441–4445PubMedCrossRefGoogle Scholar
  50. 50.
    Feuerstein N, Huang D, Prystowsky MB (1995) Rapamycin selectively blocks interleukin-2-induced proliferating cell nuclear antigen gene expression in T lymphocyte. J Biol Chem 270:9454–5458PubMedCrossRefGoogle Scholar
  51. 51.
    Nishizawa R, Takei Y, Yoshida M, Tomiyoshi T, Saizo K, Nishikawa K, Nemoto K, Takahashi K, Fujii A, Nakamura T, Takita T, Takeuchi T (1988) Synthesis and biological activity of spergualin analogues. I. J Antibiot 41:1629–1643CrossRefGoogle Scholar
  52. 52.
    Tepper MA, Betty B, Bursuker I, Pasternak RD, Cleaveland J, Spitalny GL, Schacter B (1991) Inhibition of antibody production by the immunosuppressive agent, 15-deoxyspergualin. Transplant Proc 23:328–331PubMedGoogle Scholar
  53. 53.
    Dickneite G, Schorlemmer HU, Sedlacek HH (1987) Decrease of mononuclear phagocyte cell functions and prolongation of graft survival in experimental transplantation by (+/-)-15-deoxyspergualin. Int J Immunopharmacol 9:559–565PubMedCrossRefGoogle Scholar
  54. 54.
    Tepper MA, Nadler S, Mazzucco C, Singh C, Kelley S (1993) 15-deoxyspergualin, a novel immunosuppressive drug: Studies of the mechanism of action. Ann N Y Acad Sci 685:136–147PubMedCrossRefGoogle Scholar
  55. 55.
    Nadler SG, Tepper MA, Schacter B, Mazzucco CE (1992) Interaction of the immunosuppressant deoxyspergualin with a member of the Hsp70 family of heat shock proteins. Science 258:484–486PubMedCrossRefGoogle Scholar
  56. 56.
    Suzuki CK, Bonifacino JS, Lin AY, Davis MM, Klausner RD (1991) Regulating the retention of T-cell receptor a variants within the endoplasmic reticulum: calcium-dependent association with BiP. J Cell Biol 114:189–205PubMedCrossRefGoogle Scholar
  57. 57.
    Van Buskirk AM, de Nagel DC, Guagliardi LE, Brodsky FM, Pierce SK (1991) Cellular and subcellular distribution of PBP72/74, a peptide-binding protein that plays a role in antigen processing. J Immunol 146:500–506Google Scholar
  58. 58.
    Tai PK, Alberts MW, Chang H, Faber LE, Schreiber SL (1992) Association of a 59-kilodalton immunophilin with the glucocorticoid receptor complex. Science 256:1315–1318PubMedCrossRefGoogle Scholar
  59. 59.
    Braun MY, Lowin B, French L, Acha-Orbea H, Tschopp J (1996) Cytotoxic T cells deficient in both functional Fas ligand and perforin show residual cytolytic activity yet lose their capacity to induce lethal acute graft-versus-host disease. J Exp Med 183: 657–661PubMedCrossRefGoogle Scholar
  60. 60.
    Lee RK, Spielman J, Zhao DY, Olsen KJ, Podack ER (1996) Perforin, Fas ligand, and tumor necrosis factor are the major cytotoxic molecules used by lymphokine-activated killer cells. J Immunol 157: 1919–1925PubMedGoogle Scholar
  61. 61.
    Nagata S, Golstein P (1995) The Fas death factor. Science 267: 1449–56PubMedCrossRefGoogle Scholar
  62. 62.
    Kondo T, Suda T, Fukuyama H, Adachi M, Nagata S (1997) Essential roles of the Fas ligand in the development of hepatitis. Nat Med 3: 409–413PubMedCrossRefGoogle Scholar
  63. 63.
    Giordano C, Stassi G, De Maria R, Todaro M, Richiusa P, Papoff G, Ruberti G, Bagnasco M, Testi R, Galluzzo A (1997) Potential involvement of Fas and its ligand in the pathogenesis of Hashimoto’s thyroiditis. Science 275: 960–963PubMedGoogle Scholar
  64. 64.
    Hahne M, Rimoldi D, Schröter M, Romero P, Schreier M, French LE, Schneider P, Bornand T, Fontana A, Lienard D, Cerottini JC, Tschopp J (1996) Melanoma cell expression of Fas (Apo-1/CD95) ligand: Implications for tumor immune escape. Science 274: 1363–1366PubMedCrossRefGoogle Scholar
  65. 65.
    Strand S, Hofmann WJ, Hug H, Muller M, Otto G, Strand D, Mariani SM, Stremmel W, Krammer PH, Galle PR (1996) Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells-A mechanism of immune evasion? Nat Med 2: 1361–1366PubMedCrossRefGoogle Scholar
  66. 66.
    O’Connell J, O’Sullivan GC, Collins JK, Shanahan F (1996) The Fas counterattack: Fasmediated T cell killing by colon cancer cells expressing Fas ligand. J Exp Med 184: 1075–1082PubMedCrossRefGoogle Scholar
  67. 67.
    Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schroter M, Bums K, Mattmann C, Rimoldi D, French LE, Tschopp J (1997) Inhibition of death receptor signals by cellular FLIP. Nature 388: 190–195PubMedCrossRefGoogle Scholar
  68. 68.
    Burkhardt JK, Hester S, Lapham CK, Argon Y (1990) The lytic granules of natural killer cells are dual-function organelles combining secretory and pre-lysosomal compartments. J Cell Biol 111: 2327–2340PubMedCrossRefGoogle Scholar
  69. 69.
    Peters PJ, Borst J, Oorschot V, Fukuda M, Krahenbühl O, Tschopp J, Slot JW, Geuze HJ (1991) Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes. J Exp Med 173: 1099–1109PubMedCrossRefGoogle Scholar
  70. 70.
    Masson D, Peters PJ, Geuze HJ, Borst J, Tschopp J (1990) Interaction of chondroitin sulfate with perforin and granzymes of cytolytic T-cells is dependent on pH. Biochemistry 29: 11229–11235PubMedCrossRefGoogle Scholar
  71. 71.
    Kataoka T, Sato M, Kondo S, Nagai K (1996) Estimation of pH and the number of lytic granules in a CD8+ CTL clone treated with an inhibitor of vacuolar type H+-ATPase, concanamycin A. Biosci Biotech Biochem 60: 1729–1731CrossRefGoogle Scholar
  72. 72.
    Kataoka T, Takaku K, Magae J, Shinohara N, Takayama H, Kondo S, Nagai, K (1994) Acidification is essential for maintaining the structure and function of lytic granules of CTL. J Immunol 153: 3938–3947PubMedGoogle Scholar
  73. 73.
    Kataoka T, Shinohara N, Takayama H, Takaku K, Kondo S, Yonehara S, Nagai K (1996) Concanamycin A, a powerful tool for characterization and estimation of contribution of perforin- and Fas-based lytic pathways in cell-mediated cytotoxicity. J Immunol 156: 3678–3686PubMedGoogle Scholar
  74. 74.
    Togashi K, Kataoka T, Nagai K (1997) Characterization of a series of vacuolar type H+-ATPase inhibitors on CTL-mediated cytotoxicity. Immunol Lett 55: 139–144PubMedCrossRefGoogle Scholar
  75. 75.
    Kataoka T, Togashi K, Takayama H, Takaku K, Nagai K (1997) Inactivation and proteolytic degradation of perforin within lytic granules upon neutralization of acidic pH. Immunology 91: 493–500PubMedCrossRefGoogle Scholar
  76. 76.
    Heusel JW, Wesselschmidt RL, Shresta S, Russell JH, Ley TJ (1994) Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells. Cell 76: 977–987PubMedCrossRefGoogle Scholar
  77. 77.
    Talanian RV, Yang X, Turbov J, Seth P, Ghayur T, Casiano CA, Orth K, Froelich C J (1997) Granule-mediated killing: Pathways for granzyme B-initiated apoptosis. J Exp Med 186: 1323–1331PubMedCrossRefGoogle Scholar
  78. 78.
    Sarin A, Williams MS, Alexander-Miller MA, Berzofsky JA, Zacharchuk CM, Henkart PA (1997) Target cell lysis by CTL granule exocytosis is independent of ICE/Ced-3 family proteases. Immunity 6: 209–215PubMedCrossRefGoogle Scholar
  79. 79.
    Andrade F, Roy S, Nicholson D, Thornberry N, Rosen A, Casciola-Rosen L (1998) Granzyme B directly and efficiently cleaves several downstream caspase substrates: Implications for CTL-induced apoptosis. Immunity 8: 451–460PubMedCrossRefGoogle Scholar
  80. 80.
    Nagata S (1997) Apoptosis by death factor. Cell 88: 355–365PubMedCrossRefGoogle Scholar
  81. 81.
    Yang X, Khosravi-Far R, Chang HY, Baltimore D (1997) Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell 89: 1067–1076PubMedCrossRefGoogle Scholar
  82. 82.
    Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441–446PubMedCrossRefGoogle Scholar
  83. 83.
    Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91: 479–489PubMedCrossRefGoogle Scholar
  84. 84.
    Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S (1998) A caspaseactivated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391: 43–50PubMedCrossRefGoogle Scholar
  85. 85.
    Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO J 17: 1675–1687PubMedCrossRefGoogle Scholar
  86. 86.
    Refaeli Y, Van Parijs L, London CA, Tschopp J, Abbas AK (1998) Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. Immunity 8: 615–623PubMedCrossRefGoogle Scholar
  87. 87.
    Kataoka T, Taniguchi M, Yamada A, Suzuki H, Hamada S, Magae J, Nagai K (1996) Identification of low molecular weight probes on perforin- and Fas-based killing mediated by cytotoxic T lymphocytes. Biosci Biotech Biochem 60: 1726–1728CrossRefGoogle Scholar
  88. 88.
    Kataoka T, Nagai K (1997) Characterization of perforin-based and Fas-based CTLmediated cytotoxicity by using low molecular probes. Funatsu K et al (eds.). Animal Cell Technology: Basic & Applied Aspects, 8: 547–552 Kluwer Academic PublisherCrossRefGoogle Scholar
  89. 89.
    Togashi K, Kataoka T, Nagai K (1997) Concanamycin A, a vacuolar type H+-ATPase inhibitor, induces cell death in activated CD8+ CTL. Cytotechnology 25: 127–135PubMedCrossRefGoogle Scholar
  90. 90.
    Akifusa S, Ohguchi M, Koseki T, Nara K, Semba I, Yamato K, Okahashi N, Merino R, Núñez G, Hanada N, Takehara T, Nishihara T (1998) Increase in Bcl-2 level promoted by CD40 ligation correlates with inhibition of B cell apoptosis induced by vacuolar type H+-ATPase inhibitor. Exp Cell Res 238: 82–89PubMedCrossRefGoogle Scholar
  91. 91.
    Nakamura A, Nagai K, Ando K, Tamura G (1986) Selective suppression by prodigiosin of the mitogenic response of murine splenocytes. J Antibiot 39: 1155–1159PubMedCrossRefGoogle Scholar
  92. 92.
    Nakamura A, Magae J, Tsuji RF, Yamasaki M, Nagai K (1989) Suppression of cytotoxic T cell induction in vivo by prodigiosin 25-C. Transplant 47: 1013–1016CrossRefGoogle Scholar
  93. 93.
    Tsuji RF, Yamamoto M, Nakamura A, Kataoka T, Magae J, Nagai K, Yamasaki M (1990) Selective immunosuppression of prodigiosin 25-C and FK506 in the murine immune system. J Antibiot 43: 1293–1301PubMedCrossRefGoogle Scholar
  94. 94.
    Tsuji RF, Magae J, Yamashita M, Nagai K, Yamasaki M (1992) Immunomodulating properties of prodigiosin 25-C, an antibiotic which preferentially suppresses induction of cytotoxic T cells. J Antibiot 45: 1295–1302PubMedCrossRefGoogle Scholar
  95. 95.
    Lee MH, Kataoka T, Magae J, Nagai K (1995) Prodigiosin 25-C suppression of cytotoxic T cells in vitro and in vivo similar to that of concanamycin B, a specific inhibitor of vacuolar type H+-ATPase. Biosci Biotech Biochem 59: 1417–1421CrossRefGoogle Scholar
  96. 96.
    Kataoka T, Magae J, Nariuchi H, Yamasaki M, Nagai K (1992) Enhancement by concanavalin A of the suppressive effect of prodigiosin 25-C on proliferation of murine splenocytes. J Antibiot 45: 1303–1312PubMedCrossRefGoogle Scholar
  97. 97.
    Kataoka T, Magae J, Kasamo K, Yamanishi H, Endo A, Yamasaki M, Nagai K (1992) Effects of prodigiosin 25-C on cultured cell lines: its similarity to monovalent polyether ionophores and vacuolar type H+-ATPase inhibitors. J. Antibiot 45: 1618–1625PubMedCrossRefGoogle Scholar
  98. 98.
    Songia S, Mortellaro A, Taverna S, Fornasiero C, Scheiber EA, Erba E, Colotta F, Mantovani A, Isetta AM, Golay J (1997) Characterization of the new immunosuppressive drug undecylprodigiosin in human lymphocytes: retinoblastoma protein, cyclindependent kinase-2, and cyclin-dependent kinase-4 as molecular targets. J Immunol 158: 3987–3995PubMedGoogle Scholar
  99. 99.
    Kataoka T, Muroi M, Ohkuma S, Waritani T, Magae J, Takatsuki A, Kondo S, Yamasaki M, Nagai K (1995) Prodigiosin 25-C uncouples vacuolar type 1+-ATPase, inhibits vacuolar acidification and affects glycoprotein processing. FEBS Lett 359: 53–59PubMedCrossRefGoogle Scholar
  100. 100.
    Lancki DW, Kaper BP, Fitch FW (1989) The requirements for triggering of lysis by cytolytic T lymphocyte clones II. Cyclosporin A inhibits TCR-mediated exocytosis but only selectively inhibits TCR-mediated lytic activity by cloned CTL. J Immunol 142: 416–424PubMedGoogle Scholar
  101. 101.
    Trenn G, Taffs R, Hohman R, Kincaid R, Shevach EM, Sitkovsky M (1989) Biochemical characterization of the inhibitory effect of CsA on cytolytic T lymphocyte effector functions. J Immunol 142: 3796–3802PubMedGoogle Scholar
  102. 102.
    Dutz JP, Fruman DA, Burakoff SJ, Bierer BE (1993) A role for calcineurin in degranulation of murine cytotoxic T lymphocytes. J Immunol 150: 2591–2598PubMedGoogle Scholar
  103. 103.
    Anel A, Buferne M, Boyer C, Schmitt-Verhulst AM, Golstein P (1994) T cell receptorinduced Fas ligand expression in cytotoxic T lymphocyte clones is blocked by protein tyrosine kinase inhibitors and cyclosporin A. Eur J Immunol 24: 2469–2476PubMedCrossRefGoogle Scholar
  104. 104.
    Mehta BA, Schmidt-Wolf IG, Weissman, IL, Negrin RS (1995) Two pathways of exocytosis of cytoplasmic granule contents and target cell killing by cytokine-induced CD3+ CD56+ killer cells. Blood 86: 3493–3499PubMedGoogle Scholar
  105. 105.
    Rogers AM, Thilenius AR, Russell JH (1997) Cyclosporine-insensitive partial signaling and multiple roles of Ca2+ in Fas ligand-induced lysis. J Immunol 159: 3140–3147PubMedGoogle Scholar
  106. 106.
    Burkhardt JK, McIlvain JM Jr, Sheetz MP, Argon Y (1993) Lytic granules from cytotoxic T cells exhibit kinesin-dependent motility on microtubules in vitro. J Cell Sci 104: 151–162PubMedGoogle Scholar
  107. 107.
    O’Rourke AM, Apgar JR, Kane KP, Martz E, Mescher MF (1991) Cytoskeletal function in CD8- and T cell receptor-mediated interaction of cytotoxic T lymphocytes with class I protein. J Exp Med 173: 241–249PubMedCrossRefGoogle Scholar
  108. 108.
    Valitutti S, Dessing M, Aktories K, Gallati H, Lanzavecchia A (1995) Sustained signaling leading to T cell activation results from prolonged T cell receptor occupancy. Role of T cell actin cytoskeleton. J Exp Med 181: 577–584PubMedCrossRefGoogle Scholar
  109. 109.
    Caplan S, Zeliger S, Wang L, Baniyash M (1995) Cell-surface-expressed T-cell antigenreceptor ζ chain is associated with the cytoskeleton. Proc Natl Acad Sci USA 92: 4768–4772PubMedCrossRefGoogle Scholar
  110. 110.
    Rozdzial MM, Malissen B, Finkel TH (1995) Tyrosine-phosphorylated T cell receptor ζ chain associates with the actin cytoskeleton upon activation of mature T lymphocytes. Immunity 3: 623–633PubMedCrossRefGoogle Scholar
  111. 111.
    Müllbacher A, Eichner RD (1984) Immunosuppression in vitro by a metabolite of a human pathogenic fungus. Proc Natl Acad Sci USA 81: 3835–3837PubMedCrossRefGoogle Scholar
  112. 112.
    Pahl HL, Krauß B, Schulze-Osthoff K, Decker T, Traenckner EB, Vogt M, Myers C, Parks T, Waring P, Mühlbacher A, Czernilofsky AP, Baeuerle PA (1996) The immunosuppressive fungal metabolite gliotoxin specifically inhibits transcription factor NF-κB. J Exp Med 183: 1829–1840PubMedCrossRefGoogle Scholar
  113. 113.
    Sutton P, Newcombe NR, Waring P, Müllbacher A (1994) In vivo immunosuppressive activity of gliotoxin, a metabolite produced by human pathogenic fungi. Infec Immun 62: 1192–1198Google Scholar
  114. 114.
    Waring P, Khan T, Sjaarda A (1997) Apoptosis induced by gliotoxin is preceded by phosphorylation of histone H3 and enhanced sensitivity of chromatin to nuclease digestion. J Biol Chem 272: 17929–17936PubMedCrossRefGoogle Scholar
  115. 115.
    Yamada A, Kataoka T, Nagai K (1997) Inhibition of CTL-mediated cytotoxicity by gliotoxin. Funatsu K et al (eds.). Animal Cell Technology: Basic & Applied Aspects 8: 633–637 Kluwer Academic PublishersCrossRefGoogle Scholar
  116. 116.
    Taniguchi M, Kataoka T, Suzuki H, Uramoto M, Ando M, Arao K, Magae J, Nishimura T, Otake N, Nagai K (1995) Costunolide and dehydrocostus lactone as inhibitors of killing function of cytotoxic T lymphocytes. Biosci Biotech Biochem 59: 2064–2067CrossRefGoogle Scholar
  117. 117.
    Anel A, Richieri GV, Kleinfeld AM (1994) A tyrosine phosphorylation requirement for cytotoxic T lymphocyte degranulation. J Biol Chem 269: 9506–9513PubMedGoogle Scholar
  118. 118.
    Rosato A, Zambon A, Mandruzzato S, Bronte V, Macino B, Calderazzo F, Collavo D, Zanovello P (1994) Inhibition of protein tyrosine phosphorylation prevents T-cellmediated cytotoxicity. Cell Immunol 159: 294–305PubMedCrossRefGoogle Scholar
  119. 119.
    Clément MV, Stamenkovic I (1996) Superoxide anion is a natural inhibitor of Fas-mediated cell death. EMBO J 15: 216–225PubMedGoogle Scholar
  120. 120.
    Ruiz-Ruiz MC, Izquierdo M, de Murcia G, Lopez-Rivas A (1997) Activation of protein kinase C attenuates early signals in Fas-mediated apoptosis. Eur J Immunol 27: 1442–1450PubMedCrossRefGoogle Scholar
  121. 121.
    Cuvillier O, Rosenthal DS, Smulson ME, Spiegel S (1998) Sphingosine 1-phosphate inhibits activation of caspases that cleave poly(ADP-ribose) polymerase and lamins during Fas- and ceramide-mediated apoptosis in Jurkat T lymphocytes. J Biol Chem 273: 2910–2916PubMedCrossRefGoogle Scholar
  122. 122.
    Holmström TH, Chow SC, Elo I, Coffey ET, Orrenius S, Sistonen L, Eriksson JE (1998) Suppression of Fas/APO-1-mediated apoptosis by mitogen-activated kinase signaling. J Immunol 160: 2626–2636PubMedGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 2000

Authors and Affiliations

  • Kazuo Nagai
  • Takao Kataoka

There are no affiliations available

Personalised recommendations