Properties of Cytotoxicity Mediated by CD4+, Perforin-Negative T-Lymphocyte Clones

  • Hajime Takayama


There has been a long-lasting debate about the involvement of perforin in antigen-specific, directional killing of target cells mediated by cytotoxic T lymphocytes (CTL). Perforin, a pore-forming protein found in cytolytic granules of natural killer (NK) cells and CTL lines, must be secreted from cytosolic granules by exocytosis, according to the “exocytosis model” for lymphocyte-mediated cytotoxicity. Indeed, it is reported that noncytotoxic rat basophilic leukemia cell line (RBL) became cytolytic against sheep erythrocyte target (SRBC) after transfection with perforin gene (Shiver and Henkart, 1991).


Target Cell Lysis Lymphocyte Clone Perforin Gene Cytolytic Granule Perforin Protein 
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. Acha-Orbea H, Scarpellino L, Hertig S, Dupuis M, Tschopp J (1990): Inhibition of lymphocyte mediated cytotoxicity by perforin antisense oligonucleotides. EMBO J 9: 3815–3819Google Scholar
  2. Berke G, Rosen D (1988): Highly lytic in vivo primed cytolytic T lymphocytes devoid of lytic granules and BLT-esterase activity acquire these constituents in the presence of T cell growth factors upon blast transformation in vitro. J Immunol 141: 3440–3445Google Scholar
  3. Chang JCC, Moorhead JW (1986): Hapten-specific, class II-restricted killing by cloned T cells: Direct lysis and production of a cytotoxic factor. J Immunol 136: 28262831Google Scholar
  4. Duke RC, Persechini PM, Chang S, Liu C-C, Cohen JJ, Young JD-E (1989): Purified perforin induces target cell lysis but not DNA fragmentation. J Exp Med 170: 1451–1456CrossRefGoogle Scholar
  5. Erb P, Grogg D, Troxler M, Kennedy M, Fluri M (1990): CD4+ T cell-mediated killing of MHC class II-positive antigen-presenting cells. I. Characterization of target cell recognition by in vivo or in vitro activated CD4 killer cells. J Immunol 144: 790–795Google Scholar
  6. Filippini A, Taffs RE, Sitkovsky MV (1990): Extracellular ATP in T-lymphocyte activation: Possible role in effector functions. Proc Natl Acad Sci USA 87: 8267–8271 With clarification (1991): Proc Natl Acad Sci USA 88: 6899Google Scholar
  7. Grusby MJ, Nabavi N, Wong H, Dick RF, Bluestone JA, Schotz MC, Glimcher LH (1990): Cloning of an interleukin-4 inducible gene from cytotoxic T lymphocytes and its identification as a lipase. Cell 60: 451–459CrossRefGoogle Scholar
  8. Hancock GE, Cohn ZA, Kaplan G (1989): The generation of antigen-specific, major histocompatibility complex-restricted cytotoxic T lymphocytes of the CD4+ phenotype. Enhancement by the cutaneous administration of interleukin 2. J Exp Med 169: 909–919CrossRefGoogle Scholar
  9. Hayes PM, Berrebi GA, Henkart PA (1989): Induction of target cell DNA release by the cytotoxic T lymphocyte granule protease granzyme A. J Exp Med 170: 933–946CrossRefGoogle Scholar
  10. Henkart PA, Millard PJ, Reynolds CW, Henkart M (1984): Cytolytic activity of purified cytoplasmic granules from cytotoxic rat large granular lymphocyte tumors. J Exp Med 160: 75–93CrossRefGoogle Scholar
  11. Ju S-T (1991): Distinct pathways of CD4 and CD8 cells induce rapid target DNA fragmentation. J Immunol 146: 812–818Google Scholar
  12. Ju S-T, Ruddle NH, Strack P, Dorf ME, DeKruyff RH (1990): Expression of two distinct cytolytic mechanisms among murine CD4 subsets. J Immunol 144: 23–31Google Scholar
  13. Ju S-T, Strack P, Stromquist D, DeKruyff RH (1988): Cytolytic activity of Ia-restricted T cell clones and hybridomas: Evidence for a cytolytic mechanism indepdent of interferon-y, lymphotoxin, and tumor necrosis factor-a. Cell Immunol 117: 399–413CrossRefGoogle Scholar
  14. Kawasaki A, Shinkai Y, Kuwana Y, Furuya A, Iigo Y, Hanai N, Itoh S, Yagita H, Okumura K (1990): Perforin, a pore-forming protein detectable by monoclonal antibodies, is a functional marker for killer cells. Mt Immunol 2: 677–684Google Scholar
  15. Lancki DW, Hsieh C-S, Fitch FW (1991): Mechanisms of lysis by cytotoxic T lymphocyte clones. Lytic activity and gene expression in cloned antigen-specific CD4+ and CD8+ T lymphocytes. J Immunol 146: 3242–3249Google Scholar
  16. Liu C-C, Rafii S, Granelli-Piperno A, Trapani JA, Young JD-E (1989): Perforin and serine esterase gene expression in stimulated human T cells. J Exp Med 170: 2105–2118CrossRefGoogle Scholar
  17. Maimone MM, Morrison LA, Braciale VL, Braciale TJ (1986): Features of target cell lysis by class I and class II MHC-restricted cytolytic T lymphocytes. J Immunol 137: 3639–3643Google Scholar
  18. Nakamura M, Ross DT, Briner TJ, Gefter ML (1986): Cytolytic activity of antigen-specific T cells with helper phenotype. J Immunol 136: 44–47Google Scholar
  19. Ostergaard HL, Kane KP, Mescher MF, Clark WR (1987): Cytotoxic T lymphocyte-mediated lysis without release of serine esterase: Nature 330: 71–72CrossRefGoogle Scholar
  20. Ozaki S, York-Jolley J, Kawamura H, Berzofsky JA (1987): Cloned protein antigen-specific, Ia-restricted T cells with both helper and cytolytic activities: Mechanisms of activation and killing. Cell Immunol 105: 301316Google Scholar
  21. Reynolds CW, Reichardt D, Henkart M, Millard P, Henkart PA (1987): Inhibition of NK and ADCC activity by antibodies against purified cytoplasmic granules from rat LGL tumors. J Leukocyte Biol 42: 642–652Google Scholar
  22. Shinohara N, Huang Y-Y, Muroyama A (1991): Specific suppression of antibody response by soluble protein-specific, class II-restricted cytolytic T lymphocyte clones. Eur J Immunol 21: 23–27CrossRefGoogle Scholar
  23. Shiver JW, Henkart PA (1991): A noncytotoxic mast cell tumor line exhibits potent IgE-dependent cytotoxicity after transfection with the cytolysin/perforin gene. Cell 64: 1175–1181CrossRefGoogle Scholar
  24. Smyth MJ, Ortaldo JR, Shinkai Y-I, Yagita H, Nakata M, Okumura K, Young HA (1990): Interleukin-2 induction of pore-forming protein gene expression in human peripheral blood CD8’ T cells. J Exp Med 171: 1269–1281CrossRefGoogle Scholar
  25. Strack P, Martin C, Saito S, DeKruyff RH, Ju S-T (1990): Metabolic inhibitors distinguish cytolytic activity of CD4 and CD8 clones. Eur J Immunol 20: 179–184 Takayama H, Shinohara N, Kawasaki A, Someya Y, Hanaoka S, Kojima H, Yagita H, Okumura K, Shinkai Y-I (1991): Antigen-specific directional target cell lysis by perforin-negative T lymphocyte clones. Int Immunol 3: 1149–1156Google Scholar
  26. Tite JP (1990): Evidence of a role for TNF-a in cytolysis by CD4+, class II MHC-restricted cytotoxic T cells. Immunology 71: 208–212Google Scholar
  27. Tite JP, Janeway CA, Jr (1984): Cloned helper T cells can kill B lymphoma cells in the presence of specific antigen: Ia restriction and cognate vs. noncognate interactions in cytolysis. Eur J Immunol 14: 878–886CrossRefGoogle Scholar
  28. Tite JP, Powell MB, Ruddle NH (1985): Protein-antigen specific Ia-restricted cytolytic T cells: Analysis of frequency, target cell susceptibility, and mechanism of cytolysis. J Immunol 135: 25–33Google Scholar
  29. Trenn G, Takayama H, Sitkovsky MV (1987): Exocytosis of cytolytic granules may not be required for target cell lysis by cytotoxic T-lymphocytes. Nature 330: 72–74 Watanabe M, Yoshikawa M, Hozumi N (1987): Cytotoxic function of a cloned helper T cell line. Immunol Lett 15: 133–138Google Scholar
  30. Zijlstra M, Bix M, Simister NE, Loring JM, Raulet DH, Jaenisch R (1990): ß2-Microglobulin deficient mice lack CD4–8+ cytolytic T cells. Nature 344: 742–746CrossRefGoogle Scholar

Copyright information

© Birkhäuser Boston 1993

Authors and Affiliations

  • Hajime Takayama

There are no affiliations available

Personalised recommendations