Identification of Protein Kinases and Protein Phosphatases Involved in CTL Effector Functions. “ON” and “OFF” Signaling and Immunopharmacological Implications

  • Hirotaka Sugiyama
  • Sergey Apasov
  • Guido Trenn
  • Frank Redegeld
  • Michail Sitkovsky


Biochemical studies of cytotoxic T-lymphocyte (CTL) effector functions, the description of molecular requirements, and the enzymes needed for CTL-induced target cell (TC) death are likely to shed light on the mechanisms and individual participants of practically all steps of CTL-TC interactions (Lancki et al., 1986). These mechanisms include conjugate formation, lethal hit delivery, and events leading to TC death. Identification of important regulatory molecules will also provide key targets for immunomodulation and allow for design of specific pharmacological agents.


Protein Phosphatase Phorbol Ester Okadaic Acid Granule Exocytosis Serine Esterase 
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.


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  1. Albert F, Hua C, Truneh A, Pierre M, Schmitt-Verhulst A-M (1985): Distinction between antigen receptor and IL-2 receptor triggering events in the activation of allo-reactive T cell clones with calcium ionophores and phorbol esters. J Immonol 134: 3649–3655Google Scholar
  2. Alexander DR, Cantrell DA (1989): Kinases and phosphatases in T-cell activation. Immunol Today 10: 200–205CrossRefGoogle Scholar
  3. Berrebi G, Takayama H, Sitkovsky MV (1987): Antigen-receptor interaction requirement for conjugate formation and lethal-hit triggering by cytotoxic T lymphocytes can be bypassed by protein kinase C activators and Ca2+ ionophores. Proc Natl Acad Sci USA 84: 1364–1368CrossRefGoogle Scholar
  4. Cohen P, Holmes CFB, Tsukitan Y (1990): Okadaic acid: A new probe for the study of cellular regulation. Trends Bionchem Sci 15: 98–102CrossRefGoogle Scholar
  5. Dustin ML, Springer TA (1989): T-cell receptor cross-linking transiently stimulates adhesiveness through LFA-l. Nature 341: 619–624CrossRefGoogle Scholar
  6. Freedman R (1989): A protein with many functions? Nature 337: 407CrossRefGoogle Scholar
  7. Friedman J, Weissman I (1991): Two cytoplasmic candidates for immunophilin action are revealed by affinity for a new cyclophilin: One in the presence and one in the absence of CsA. Cell 66: 799–806CrossRefGoogle Scholar
  8. Gray LS, Gnarra JR, Engelhard VM (1987): Demonstration of a calcium influx in cytolytic T lymphocytes in response to target cell binding. J Immunol 138: 63–69Google Scholar
  9. June CH (1991): Signal transduction in T cells. Curr Opinion Immunol 3: 287–293CrossRefGoogle Scholar
  10. Kincaid R, Takayama H, Billingsley ML, Sitkovsky MV (1987): Differential expression of calmodulin-binding proteins in B, T lymphocytes and thymocytes. Nature 330: 176–178CrossRefGoogle Scholar
  11. Lancki DW, Weiss A, Fitch FW (1986): Requirements for triggering of lysis by cytolytic T lymphocyte clones. J Immunol 138: 3646–3653Google Scholar
  12. Lanzavecchia A (1986): Is the T-cell receptor involved in T-cell killing? Nature 319: 778–780CrossRefGoogle Scholar
  13. Liu J, Farmer JD, Lane WS, Friedman J, Weissman I, Schreiber SL (1991): Caícineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66: 807–815CrossRefGoogle Scholar
  14. Masson D, Tschopp J (1987): A family of serine esterases in lytic granules of cytolytic T lymphocytes. Cell 49: 679–685CrossRefGoogle Scholar
  15. Oettgen HC, Terhost C, Cantley LC, Rosoff PM (1985): Stimulation of the T3-T cell receptor complex induces a membrane-potential sensitive calcium influx. Cell 40: 583–590CrossRefGoogle Scholar
  16. O’Rourke AM, Mesher MF (1988): T-cell receptor-mediated signaling occurs in the absence of inositol phosphate production. J Biol Chem 263: 18594–18597Google Scholar
  17. Ostergaard HL, Kane KP, Mesher MF, Clark WE (1987): Cytotoxic T-lymphocyte mediated lysis without release of serine esterase. Nature 330: 71–73CrossRefGoogle Scholar
  18. Pasternack M, Verret CR, Liu MA, Eisen HN (1986): Serine esterase in cytolytic T lymphocytes. Nature 322: 740–743CrossRefGoogle Scholar
  19. Podack ER, Konigsberg PJ (1984): Cytolytic T cell granules. Isolation, structural, biochemical, and functional characterization. J Exp Med 160: 695–710CrossRefGoogle Scholar
  20. Rudd CE (1990): CD4, CD8 and the TCR-CD3 complex: A novel class of protein-tyrosine kinase receptor. Immuni Today 11: 400–406CrossRefGoogle Scholar
  21. Russell JH (1986): Phorbol-ester stimulated lysis of weak and nonspecific target cells by cytotoxic T lymphocytes. J Immunol 136: 23–27Google Scholar
  22. Schrezenmeier H, Ahnert-Hilger G, Fleischer B (1988): A T-cell receptor associated GTP-binding protein triggers TCR-mediated granule exocytosis in cytotoxic T lymphocytes. J Immunol 141: 3785–3790Google Scholar
  23. Sitkovsky MV (1988): Mechanistic, functional and immunopharmacological implications of biochemical studies of antigen receptor-triggered cytolytic T-lymphocyte activation. Immunol Rev 103: 127–160CrossRefGoogle Scholar
  24. Sitkovsky MV, Trenn G, Takayama H (1988): Cyclic AMP-dependent protein kinase as part of the possible down-regulating pathway in the antigen receptor-regulated cytotoxic T lymphocyte conjugate formation and granule exocytosis. Ann NY Acad Sci 532: 350–358CrossRefGoogle Scholar
  25. Spits H, Schooten W, Keizer H, Seventer G, deRijn M, Terhorst C, deVries JE (1986): Alloantigen recognition is preceded by non-specific adhesion of cytotoxic T-cells and target cells. Science 232: 403–405CrossRefGoogle Scholar
  26. Taffs RE, Redegeld F, Sitkovsky MV (1991): Modulation of the effector functions of cytolytic T-lymphocytes by an inhibitor of serine/threonine phosphatase, okadaic acid. J Immunol 147: 722–729Google Scholar
  27. Taffs RE, Sitkovsky MV (1991): Granule enzyme exocytosis assay for cytotoxic T lymphocyte activation. In: Current Protocols in Immunology, Coligan J, Kruisbeek AM, Margulies DH, Shevach EM, Strober W, eds. New York: Wiley InterscienceGoogle Scholar
  28. Takayama H, Sitkovsky MV (1987): Antigen receptor-regulated exocytosis in cytotoxic T lymphocytes. J Exp Med 166: 725–743CrossRefGoogle Scholar
  29. Takayama H, Trenn G, Humphrey W. Bluestone JA, Henkart PA, Sitkovsky MV (1987a): Antigen receptor —triggered secretion of a trypsin-type esterase from cytotoxic T-lymphocytes. J Immunol 138: 566–569Google Scholar
  30. Takayama H, Trenn G, Sitkovsky MV (1987b): A novel cytotoxic T lymphocyte activation assay. Optimized conditions for the antigen receptor triggered granule enzyme secretion. JImmunol Methods 104: 183–190CrossRefGoogle Scholar
  31. Takayama H, Trenn G, Sitkovsky MV (1988): locus of inhibitory action of cAMP-dependent protein kinase in the antigen receptor triggered cytotoxic T-lymphocyte activation pathway. J Biol Chem 263: 2330–2336Google Scholar
  32. Trenn G, Taffs R, Hohmann 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: 3796–3802Google Scholar
  33. 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: 72–74CrossRefGoogle Scholar
  34. Treves S, Di Virgilio F, Cerundolo V, Zanovello P, Collavo D, Pozzan T (1987): Calcium and inositol phosphates in the activation of T-cell mediated cytotoxicity. J Exp Med 166: 33–42CrossRefGoogle Scholar
  35. Trunch A, Albert F, Goldstein P, Schmidt-Verhulst AM (1985): Early steps of lymphocyte activation bypassed by synergy between calcium ionophores and phorbol ester. Nature 313: 318–320CrossRefGoogle Scholar
  36. Utsunomiya N, Tsuboi M, Nakanishi M (1986): Early transmembrane events in alloimmune cytotoxic T lymphocyte activation as revealed by stopped-flow fluorometry. Proc Natl Acad Sci USA 83: 1877–1880CrossRefGoogle Scholar
  37. Young JD-E, Leong LG, Liu CC, Damiano A, Cohn ZA (1986): Extracellular release of lymphocyte cytolytic pore—forming protein (perforin) after ionophore stimulation. Proc Natl Acad Sci USA 83: 5668–5672CrossRefGoogle Scholar

Copyright information

© Birkhäuser Boston 1993

Authors and Affiliations

  • Hirotaka Sugiyama
  • Sergey Apasov
  • Guido Trenn
  • Frank Redegeld
  • Michail Sitkovsky

There are no affiliations available

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