Perforin: More than Just a Pore-Forming Protein

REFERENCES

• ER Podack, JD Young, and ZA Cohn. Isolation and biochemical and functional characterization of perforin 1 from cytolytic T-cell granules. Proc Natl Acad Sci U S A 1985;82:8629–8633.
   PubMed Web of Science ®Google Scholar
• D Masson and J Tschopp. Isolation of a lytic, pore-forming protein (perforin) from cytolytic T-lymphocytes. J Biol Chem 1985;260:9069–9072.
   PubMed Web of Science ®Google Scholar
• JD Young, CC Liu, LG Leong, and ZA Cohn. The pore-forming protein (perforin) of cytolytic T lymphocytes is immunologically related to the components of membrane attack complex of complement through cysteine-rich domains. J Exp Med 1986;164:2077–2082.
   PubMed Web of Science ®Google Scholar
• JD Young, ZA Cohn, and ER Podack. The ninth component of complement and the pore-forming protein (perforin 1) from cytotoxic T cells: Structural, immunological, and functional similarities. Science 1986;233:184–190.
   PubMedGoogle Scholar
• PD Young, ER Podack, and ZA Cohn. Properties of a purified pore-forming protein (perforin 1) isolated from H-2-restricted cytotoxic T cell granules. J Exp Med 1986;164:144–155.
   PubMedGoogle Scholar
• O Binah, CC Liu, JD Young, and G Berke. Channel formation and [Ca2+]i accumulation induced by perforin N-terminus peptides: Comparison with purified perforin and whole lytic granules. Biochem Biophys Res Commun 1997;240:647–650.
   PubMedGoogle Scholar
• S Apasov, F Redegeld, and M Sitkovsky. Cell-mediated cytotoxicity: Contact and secreted factors. Curr Opin Immunol 1993;5:404–410.
   PubMed Web of Science ®Google Scholar
• MT Esser, DM Haverstick, CL Fuller, Ca2+ signaling modulates cytolytic T lymphocyte effector functions. J Exp Med 1998;187:1057–1067.
   PubMed Web of Science ®Google Scholar
• A Hameed, KJ Olsen, MK Lee, Cytolysis by Ca-permeable transmembrane channels. Pore formation causes extensive DNA degradation and cell lysis. J Exp Med 1989;169:765–777.
   PubMed Web of Science ®Google Scholar
• J Tschopp, S Schafer, D Masson, Phosphorylcholine acts as a Ca2+-dependent receptor molecule for lymphocyte perforin. Nature 1989;337:272–274.
   PubMedGoogle Scholar
• JD Young, WR Clark, CC Liu, and ZA Cohn. A calcium- and perforin-independent pathway of killing mediated by murine cytolytic lymphocytes. J Exp Med 1987;166:1894–1899.
   PubMed Web of Science ®Google Scholar
• DM Kranz, MS Pasternack, and HN Eisen. Recognition and lysis of target cells by cytotoxic T lymphocytes. Fed Proc 1987;46:309–312.
   PubMedGoogle Scholar
• MA Hadders, DX Beringer, and P Gros. Structure of C8alpha-MACPF reveals mechanism of membrane attack in complement immune defense. Science 2007;317:1552–1554.
   PubMed Web of Science ®Google Scholar
• CJ Rosado, AM Buckle, RH Law, A common fold mediates vertebrate defense and bacterial attack. Science 2007;317:1548–1551.
   PubMed Web of Science ®Google Scholar
• I Voskoboinik, MC Thia, J Fletcher, Calcium-dependent plasma membrane binding and cell lysis by perforin are mediated through its C2 domain: A critical role for aspartate residues 429, 435, 483, and 485 but not 491. J Biol Chem 2005;280:8426–8434.
   PubMed Web of Science ®Google Scholar
• G Berke and D Rosen. 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 1988;141:1429–1436.
   PubMedGoogle Scholar
• DE Jenne and J Tschopp. Granzymes, a family of serine proteases released from granules of cytolytic T lymphocytes upon T cell receptor stimulation. Immunol Rev 1988;103:53–71.
   PubMed Web of Science ®Google Scholar
• D Masson and J Tschopp. A family of serine esterases in lytic granules of cytolytic T lymphocytes. Cell 1987;49:679–685.
   PubMed Web of Science ®Google Scholar
• CS Guy, SL Rankin, J Wang, and TI Michalak. Hepatocytes can induce death of contacted cells via perforin-dependent mechanism. Hepatology 2008;47:1691–1701.
   PubMedGoogle Scholar
• D Kagi, B Ledermann, K Burki, Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 1994;369:31–37.
   PubMed Web of Science ®Google Scholar
• S Potter, T Chan-Ling, HJ Ball, Perforin mediated apoptosis of cerebral microvascular endothelial cells during experimental cerebral malaria. Int J Parasitol 2006;36:485–496.
   PubMed Web of Science ®Google Scholar
• SB Jiang, PM Persechini, A Zychlinsky, Resistance of cytolytic lymphocytes to perforin-mediated killing. Lack of correlation with complement-associated homologous species restriction. J Exp Med 1988;168:2207–2219.
   PubMedGoogle Scholar
• NL Allbritton, C Nagler-Anderson, TJ Elliott, Target cell lysis by cytotoxic T lymphocytes that lack detectable hemolytic perforin activity. J Immunol 1988;141:3243–3248.
   PubMedGoogle Scholar
• D Chowdhury and J Lieberman. Death by a thousand cuts: Granzyme pathways of programmed cell death. Annu Rev Immunol 2008;26:389–420.
   PubMed Web of Science ®Google Scholar
• ER Podack, DM Lowrey, M Lichtenheld, and A Hameed. Function of granule perforin and esterases in T cell-mediated reactions. Components required for delivery of molecules to target cells. Ann N Y Acad Sci 1988;532:292–302.
   PubMedGoogle Scholar
• RC Duke, PM Persechini, and S Chang. Purified perforin induces target cell lysis but not DNA fragmentation. J Exp Med 1989;170:1451–1456.
   PubMed Web of Science ®Google Scholar
• S Jiang, PM Persechini, B Perussia, and JD Young. Resistance of cytolytic lymphocytes to perforin-mediated killing. Murine cytotoxic T lymphocytes and human natural killer cells do not contain functional soluble homologous restriction factor or other specific soluble protective factors. J Immunol 1989;143:1453–1460.
   PubMedGoogle Scholar
• PM Persechini, CC Liu, S Jiang, and JD Young. The lymphocyte pore-forming protein perforin is associated with granules by a pH-dependent mechanism. Immunol Lett 1989;22:23–27.
   PubMed Web of Science ®Google Scholar
• CC Liu, S Jiang, PM Persechini, Resistance of cytolytic lymphocytes to perforin-mediated killing. Induction of resistance correlates with increase in cytotoxicity. J Exp Med 1989;169:2211–2225.
   PubMedGoogle Scholar
• P Bolitho, I Voskoboinik, JA Trapani, and MJ Smyth. Apoptosis induced by the lymphocyte effector molecule perforin. Curr Opin Immunol 2007;19:339–347.
   Google Scholar
• ME Pipkinj and J Lieberman. Delivering the kiss of death: Progress on understanding how perforin works. Curr Opin Immunol 2007;19:301–308.
   PubMedGoogle Scholar
• M Catalfamo and PA Henkart. Perforin and the granule exocytosis cytotoxicity pathway. Curr Opin Immunol 2003;15:522–527.
   PubMedGoogle Scholar
• SM Raja, SS Metkar, and CJ Froelich. Cytotoxic granule-mediated apoptosis: Unraveling the complex mechanism. Curr Opin Immunol 2003;15:528–532.
   PubMedGoogle Scholar
• SS Metkar, B Wang, M Aguilar-Santelises, Cytotoxic cell granule-mediated apoptosis: Perforin delivers granzyme B-serglycin complexes into target cells without plasma membrane pore formation. Immunity 2002;16:417–428.
   PubMed Web of Science ®Google Scholar
• J Lieberman. The ABCs of granule-mediated cytotoxicity: New weapons in the arsenal. Nat Rev Immunol 2003;3:361–370.
   PubMed Web of Science ®Google Scholar
• K Veugelers, B Motyka, C Frantz, The granzyme B-serglycin complex from cytotoxic granules requires dynamin for endocytosis. Blood 2004;103:3845–3853.
   PubMedGoogle Scholar
• D Masson, PJ Peters, HJ Geuze, Interaction of chondroitin sulfate with perforin and granzymes of cytolytic T-cells is dependent on pH. Biochemistry 1990;29:11229–11235.
   PubMedGoogle Scholar
• JD Young, A Damiano, MA DiNome, Dissociation of membrane binding and lytic activities of the lymphocyte pore-forming protein (perforin). J Exp Med 1987;165:1371–82.
   PubMed Web of Science ®Google Scholar
• J Tschopp and D Masson. Inhibition of the lytic activity of perforin (cytolysin) and of late complement components by proteoglycans. Mol Immunol 1987;24:907–913.
   PubMedGoogle Scholar
• JP Galvin, LH Spaeny-Dekking, B Wang, Apoptosis induced by granzyme B-glycosaminoglycan complexes: Implications for granule-mediated apoptosis in vivo. J Immunol 1999;162:5345–5350.
   PubMedGoogle Scholar
• EH Spaeny-Dekking, AM Kamp, CJ Froelich, and CE Hack. Extracellular granzyme A, complexed to proteoglycans, is protected against inactivation by protease inhibitors. Blood 2000;95:1465–1472.
   PubMedGoogle Scholar
• B Lowin, O Krahenbuhl, C Muller, Perforin and its role in T lymphocyte-mediated cytolysis. Experientia 1992;48:911–920.
   PubMedGoogle Scholar
• SM Raja, B Wang, M Dantuluri, Cytotoxic cell granule-mediated apoptosis. Characterization of the macromolecular complex of granzyme B with serglycin. J Biol Chem 2002;277:49523–49530.
   PubMedGoogle Scholar
• RH Clark, JC Stinchcombe, A Day, Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol 2003;4:1111–1120.
   PubMed Web of Science ®Google Scholar
• M Faroudi, C Utzny, M Salio, Lytic versus stimulatory synapse in cytotoxic T lymphocyte/target cell interaction: Manifestation of a dual activation threshold. Proc Natl Acad Sci U S A 2003;100:14145–14150.
   PubMed Web of Science ®Google Scholar
• M Marcet-Palacios, SO Odemuyiwa, JJ Coughlin, Vesicle-associated membrane protein 7 (VAMP-7) is essential for target cell killing in a natural killer cell line. Biochem Biophys Res Commun 2008;366:617–623.
   PubMedGoogle Scholar
• JA Trapani and MJ Smyth. Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol 2002;2:735–747.
   PubMed Web of Science ®Google Scholar
• T Kataoka, K Takaku, J Magae, Acidification is essential for maintaining the structure and function of lytic granules of CTL. Effect of concanamycin A, an inhibitor of vacuolar type H(+)-ATPase, on CTL-mediated cytotoxicity. J Immunol 1994;153:3938–3947.
   PubMed Web of Science ®Google Scholar
• JH Russell and TJ Ley. Lymphocyte-mediated cytotoxicity. Annu Rev Immunol 2002;20:323–370.
   PubMed Web of Science ®Google Scholar
• M Dupuis, E Schaerer, KH Krause, and J Tschopp. The calcium-binding protein calreticulin is a major constituent of lytic granules in cytolytic T lymphocytes. J Exp Med 1993;177:1–7.
   PubMed Web of Science ®Google Scholar
• F Yoshimura and T Suzuki. Calcium-stimulated adenosine triphosphatase in the microsomal fraction of tooth germ from porcine fetus. Biochim Biophys Acta 1975;410:167–177.
   Google Scholar
• NJ Waterhouse and JA Trapani. CTL: Caspases Terminate Life, but that's not the whole story. Tissue Antigens 2002;59:175–183.
   PubMedGoogle Scholar
• J Pardo, S Balkow, A Anel, and MM Simon. Granzymes are essential for natural killer cell-mediated and perf-facilitated tumor control. Eur J Immunol 2002;32:2881–2887.
   PubMedGoogle Scholar
• M Merger, JL Viney, R Borojevic, Defining the roles of perforin, Fas/FasL, and tumour necrosis factor alpha in T cell induced mucosal damage in the mouse intestine. Gut 2002;51:155–163.
   PubMed Web of Science ®Google Scholar
• G Kurys, Y Tagaya, R Bamford, The long signal peptide isoform and its alternative processing direct the intracellular trafficking of interleukin-15. J Biol Chem 2000;275:30653–30659.
   PubMedGoogle Scholar
• C Siggaard, S Rittig, TJ Corydon, Clinical and molecular evidence of abnormal processing and trafficking of the vasopressin preprohormone in a large kindred with familial neurohypophyseal diabetes insipidus due to a signal peptide mutation. J Clin Endocrinol Metab 1999;84:2933–2941.
   PubMedGoogle Scholar
• G Berke. The CTL's kiss of death. Cell 1995;81:9–12.
   PubMed Web of Science ®Google Scholar
• JL Stow, JB de Almeida, N Narula, A heterotrimeric G protein, G alpha i-3, on Golgi membranes regulates the secretion of a heparan sulfate proteoglycan in LLC-PK1 epithelial cells. J Cell Biol 1991;114:1113–1124.
   PubMedGoogle Scholar
• L De Vries, E Elenko, JM McCaffery, RGS-GAIP, a GTPase-activating protein for Galphai heterotrimeric G proteins, is located on clathrin-coated vesicles. Mol Biol Cell 1998;9:1123–1134.
   PubMedGoogle Scholar
• F Wylie, K Heimann, TL Le, GAIP, a Galphai-3-binding protein, is associated with Golgi-derived vesicles and protein trafficking. Am J Physiol 1999;276:C497–C506.
   Google Scholar
• TK Chatterjee and RA Fisher. Cytoplasmic, nuclear, and golgi localization of RGS proteins. Evidence for N-terminal and RGS domain sequences as intracellular targeting motifs. J Biol Chem 2000;275:24013–24021.
   PubMedGoogle Scholar
• JC Lang and T Costa. Distribution of the alpha-subunit of the guanine nucleotide-binding protein Gi2 and its comparison to G alpha o. J Recept Res 1989;9:313–329.
   PubMed Web of Science ®Google Scholar
• N Nausch and A Cerwenka. NKG2D ligands in tumor immunity. Oncogene 2008;27:5944–5958.
   PubMed Web of Science ®Google Scholar
• P Borrow. Mechanisms of viral clearance and persistence. J Viral Hepat 4 Suppl 1997;2:16–24.
   Google Scholar
• N Nausch, L Florin, B Hartenstein, Cutting edge: The AP-1 subunit JunB determines NK cell-mediated target cell killing by regulation of the NKG2D-ligand RAE-1epsilon. J Immunol 2006;176:7–11.
   PubMedGoogle Scholar
• JF de Vries, PA von dem Borne, SA van Luxemburg-Heijs, Differential activation of the death receptor pathway in human target cells induced by cytotoxic T lymphocytes showing different kinetics of killing. Haematologica 2007;92:1671–1678.
   PubMedGoogle Scholar
• JA Trapani and VR Sutton. Granzyme B: Pro-apoptotic, antiviral and antitumor functions. Curr Opin Immunol 2003;15:533–543.
   PubMed Web of Science ®Google Scholar
• E Lannan, R Vandergaast, and PD Friesen. Baculovirus caspase inhibitors P49 and P35 block virus-induced apoptosis downstream of effector caspase DrICE activation in Drosophila melanogaster cells. J Virol 2007;81:9319–9330.
   PubMedGoogle Scholar
• S Thoma-Uszynski, S Stenger, and RL Modlin. CTL-mediated killing of intracellular Mycobacterium tuberculosis is independent of target cell nuclear apoptosis. J Immunol 2000;165:5773–5779.
   PubMedGoogle Scholar
• G Dorothee, M Ameyar, A Bettaieb, Role of Fas and granule exocytosis pathways in tumor-infiltrating T lymphocyte-induced apoptosis of autologous human lung-carcinoma cells. Int J Cancer 2001;91:772–777.
   PubMedGoogle Scholar
• G MacDonald, L Shi, C Vande Velde, Mitochondria-dependent and -independent regulation of Granzyme B-induced apoptosis. J Exp Med 1999;189:131–144.
   PubMed Web of Science ®Google Scholar
• JA Heibein, M Barry, B Motyka, and RC Bleackley. Granzyme B-induced loss of mitochondrial inner membrane potential (Delta Psi m) and cytochrome c release are caspase independent. J Immunol 1999;163:4683–4693.
   PubMed Web of Science ®Google Scholar
• KA Browne, E Blink, VR Sutton, Cytosolic delivery of granzyme B by bacterial toxins: Evidence that endosomal disruption, in addition to transmembrane pore formation, is an important function of perforin. Mol Cell Biol 1999;19:8604– 8615.
   PubMed Web of Science ®Google Scholar
• L Wagner, RK Avery, L Bensinger, Inhibition of cytotoxic T-lymphocyte-triggered apoptosis by target cell surface-coupled aprotinin. Mol Immunol 1995;32:853–864.
   PubMedGoogle Scholar
• JA Kummer, O Micheau, P Schneider, Ectopic expression of the serine protease inhibitor PI9 modulates death receptor-mediated apoptosis. Cell Death Differ 2007;14:1486–1496.
   PubMedGoogle Scholar
• JP Medema, J de Jong, LT Peltenburg, Blockade of the granzyme B/perforin pathway through overexpression of the serine protease inhibitor PI-9/SPI-6 constitutes a mechanism for immune escape by tumors. Proc Natl Acad Sci U S A 2001;98:11515–11520.
   PubMed Web of Science ®Google Scholar
• R Godal, U Keilholz, L Uharek, Lymphomas are sensitive to perforin-dependent cytotoxic pathways despite expression of PI-9 and overexpression of bcl-2. Blood 2006;107:3205–3211.
   PubMedGoogle Scholar
• CE Hirst, MS Buzza, VR Sutton, Perforin-independent expression of granzyme B and proteinase inhibitor 9 in human testis and placenta suggests a role for granzyme B-mediated proteolysis in reproduction. Mol Hum Reprod 2001;7:1133–1142.
   PubMed Web of Science ®Google Scholar
• T Muthukumar, R Ding, D Dadhania, Serine proteinase inhibitor-9, an endogenous blocker of granzyme B/perforin lytic pathway, is hyperexpressed during acute rejection of renal allografts. Transplantation 2003;75:1565–1570.
   PubMed Web of Science ®Google Scholar
• KN Balaji, N Schaschke, W Machleidt, Surface cathepsin B protects cytotoxic lymphocytes from self-destruction after degranulation. J Exp Med 2002;196:493–503.
   PubMed Web of Science ®Google Scholar
• L Chen, M Woo, R Hakem, and RG Miller. Perforin-dependent activation-induced cell death acts through caspase 3 but not through caspases 8 or 9. Eur J Immunol 2003;33:769–778.
   PubMedGoogle Scholar
• MB Barrie, HW Stout, MS Abougergi, Antiviral cytokines induce hepatic expression of the granzyme B inhibitors, proteinase inhibitor 9 and serine proteinase inhibitor 6. J Immunol 2004;172:6453–6459.
   PubMedGoogle Scholar
• D Kagi, B Odermatt, and TW Mak. Homeostatic regulation of CD8+ T cells by perforin. Eur J Immunol 1999;29:3262–3272.
   PubMed Web of Science ®Google Scholar
• VP Badovinac, SE Hamilton, and JT Harty. Viral infection results in massive CD8+ T cell expansion and mortality in vaccinated perforin-deficient mice. Immunity 2003;18:463–474.
   PubMed Web of Science ®Google Scholar
• E Roth and H Pircher. IFN-gamma promotes Fas ligand- and perforin-mediated liver cell destruction by cytotoxic CD8 T cells. J Immunol 2004;172:1588–1594.
   PubMed Web of Science ®Google Scholar
• D Kagi, B Ledermann, K Burki, Molecular mechanisms of lymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo. Annu Rev Immunol 1996;14:207–232.
   PubMed Web of Science ®Google Scholar
• WR Clark, CM Walsh, AA Glass, Cell-mediated cytotoxicity in perforin-less mice. Int Rev Immunol 1995;13:1–14.
   PubMedGoogle Scholar
• S Zhou, R Ou, L Huang, and D Moskophidis. Critical role for perforin-, Fas/FasL-, and TNFR1-mediated cytotoxic pathways in down-regulation of antigen-specific T cells during persistent viral infection. J Virol 2002;76:829–840.
   PubMedGoogle Scholar
• LH Young, LS Klavinskis, MB Oldstone, and JD Young. In vivo expression of perforin by CD8+ lymphocytes during an acute viral infection. J Exp Med 1989;169:2159–2171.
   PubMedGoogle Scholar
• J Yang, SP Huck, RS McHugh, Perforin-dependent elimination of dendritic cells regulates the expansion of antigen-specific CD8+ T cells in vivo. Proc Natl Acad Sci U S A 2006;103:147–152.
   PubMed Web of Science ®Google Scholar
• Y Tsunetsugu-Yokota, H Tamura, M Tachibana, Selective expansion of perforin-positive CD8+ T cells by immature dendritic cells infected with live Bacillus Calmette-Guerin mycobacteria. J Leukoc Biol 2002;72:115–124.
   PubMedGoogle Scholar
• B Ludewig, WV Bonilla, T Dumrese, Perforin-independent regulation of dendritic cell homeostasis by CD8(+) T cells in vivo: Implications for adaptive immunotherapy. Eur J Immunol 2001;31:1772–1779.
   PubMedGoogle Scholar
• CN Baxevanis, IF Voutsas, OE Tsitsilonis, Compromised anti-tumor responses in tumor necrosis factor-alpha knockout mice. Eur J Immunol 2000;30:1957–1966.
   PubMedGoogle Scholar
• A Kelso, EO Costelloe, BJ Johnson, The genes for perforin, granzymes A–C and IFN-gamma are differentially expressed in single CD8(+) T cells during primary activation. Int Immunol 2002;14:605–613.
   PubMedGoogle Scholar
• J Geginat, A Lanzavecchia, and F Sallusto. Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines. Blood 2003;101:4260–4266.
   PubMed Web of Science ®Google Scholar
• Z Su, MV Peluso, SH Raffegerst, Antigen presenting cells transfected with LMP2a RNA induce CD4+ LMP2a-specific cytotoxic T lymphocytes which kill via a Fas-independent mechanism. Leuk Lymphoma 2002;43:1651–1662.
   PubMed Web of Science ®Google Scholar
• K Tazume, M Hagihara, B Gansuvd, Induction of cytomegalovirus-specific CD4 +cytotoxic T lymphocytes from seropositive or negative healthy subjects or stem cell transplant recipients. Exp Hematol 2004;32:95–103.
   PubMedGoogle Scholar
• MA Suni, SA Ghanekar, DW Houck, CD4(+)CD8(dim) T lymphocytes exhibit enhanced cytokine expression, proliferation and cytotoxic activity in response to HCMV and HIV-1 antigens. Eur J Immunol 2001;31:2512–2520.
   PubMedGoogle Scholar
• G Xanthou, NI Tapinos, M Polihronis, CD4 cytotoxic and dendritic cells in the immunopathologic lesion of Sjogren's syndrome. Clin Exp Immunol 1999;118:154–163.
   PubMed Web of Science ®Google Scholar
• M Bots, E de Bruin, MT Rademaker-Koot, and JP Medema. Proteinase inhibitor-9 expression is induced by maturation in dendritic cells via p38 MAP kinase. Hum Immunol 2007;68:959–964.
   PubMedGoogle Scholar
• A Mullbacher. Cell-mediated cytotoxicity in recovery from poxvirus infections. Rev Med Virol 2003;13:223–232.
   PubMedGoogle Scholar
• CH Bird, VR Sutton, J Sun, Selective regulation of apoptosis: The cytotoxic lymphocyte serpin proteinase inhibitor 9 protects against granzyme B-mediated apoptosis without perturbing the Fas cell death pathway. Mol Cell Biol 1998;18:6387–6398.
   PubMed Web of Science ®Google Scholar
• K Baetz, S Isaaz, and GM Griffiths. Loss of cytotoxic T lymphocyte function in Chediak-Higashi syndrome arises from a secretory defect that prevents lytic granule exocytosis. J Immunol 1995;154:6122–6131.
   PubMed Web of Science ®Google Scholar
• F Mami-Chouaib, C Flament, C Asselin-Paturel, TCR alpha/beta and TCR gamma/delta CD4-/CD8- HLA-DR alloreactive CTL clones do not use Fas/Fas ligand pathway to lyse their specific target cells. Hum Immunol 1996;51: 13–22.
   PubMedGoogle Scholar
• C Cagiannos, R Zhong, Z Zang, Effect of major histocompatibility complex expression on murine intestinal graft survival. Transplantation 1998;66:1369–1374.
   PubMedGoogle Scholar
• I Cruz, CJ Meijer, JM Walboomers, Lack of MHC class I surface expression on neoplastic cells and poor activation of the secretory pathway of cytotoxic cells in oral squamous cell carcinomas. Br J Cancer 1999;81:881–889.
   PubMedGoogle Scholar
• IM Medana, A Gallimore, A Oxenius, MHC class I-restricted killing of neurons by virus-specific CD8+ T lymphocytes is effected through the Fas/FasL, but not the perforin pathway. Eur J Immunol 2000;30:3623–3633.
   PubMed Web of Science ®Google Scholar
• D Luo, D Vermijlen, PJ Kuppen, and E Wisse. MHC class I expression protects rat colon carcinoma cells from hepatic natural killer cell-mediated apoptosis and cytolysis, by blocking the perforin/granzyme pathway. Comp Hepatol 2002;1:2.
   PubMedGoogle Scholar
• Y Higaki, O Yamada, T Okamura, Granzyme-B-containing lymphocyte involvement in epidermal injury in graft-versus-host disease. Dermatology 2001;202:94–98.
   PubMedGoogle Scholar
• BR Blazar, CJ Lees, PJ Martin, Host T cells resist graft-versus-host disease mediated by donor leukocyte infusions. J Immunol 2000;165:4901–4909.
   PubMedGoogle Scholar
• K Saigo and R Ryo. Therapeutic strategy for post-transfusion graft-vs.-host disease. Int J Hematol 1999;69:147–151.
   PubMedGoogle Scholar
• A Shustov, P Nguyen, F Finkelman, Differential expression of Fas and Fas ligand in acute and chronic graft-versus-host disease: Up-regulation of Fas and Fas ligand requires CD8+ T cell activation and IFN-gamma production. J Immunol 1998;161:2848–2855.
   PubMed Web of Science ®Google Scholar
• JT Opferman, BT Ober, R Narayanan, and PG Ashton-Rickardt. Suicide induced by cytolytic activity controls the differentiation of memory CD8(+) T lymphocytes. Int Immunol 2001;13:411–419.
   Google Scholar
• D Spaner, K Raju, B Rabinovich, and RG Miller. A role for perforin in activation-induced T cell death in vivo: Increased expansion of allogeneic perforin-deficient T cells in SCID mice. J Immunol 1999;162:1192–1199.
   PubMed Web of Science ®Google Scholar
• D Binder, MF Van Den Broek, D Kagi, Aplastic anemia rescued by exhaustion of cytokine-secreting CD8+ T cells in persistent infection with lymphocytic choriomeningitis virus. J Exp Med 1998;187:1903–1920.
   PubMed Web of Science ®Google Scholar
• U Karrer, A Althage, B Odermatt, et al. On the key role of secondary lymphoid organs in antiviral immune responses studied in alymphoplastic (aly/aly) and spleenless (Hox11(−)/−) mutant mice. J Exp Med 1997;185:2157–2170.
   PubMed Web of Science ®Google Scholar
• S Ehl, P Klenerman, P Aichele, A functional and kinetic comparison of antiviral effector and memory cytotoxic T lymphocyte populations in vivo and in vitro. Eur J Immunol 1997;27:3404–3413.
   PubMedGoogle Scholar
• M von Herrath, B Coon, D Homann, Thymic tolerance to only one viral protein reduces lymphocytic choriomeningitis virus-induced immunopathology and increases survival in perforin-deficient mice. J Virol 1999;73:5918– 5925.
   PubMedGoogle Scholar
• SH Gregory and CC Liu. CD8+ T-cell-mediated response to Listeria monocytogenes taken up in the liver and replicating within hepatocytes. Immunol Rev 2000;174:112–122.
   PubMed Web of Science ®Google Scholar
• ER Jensen, AA Glass, WR Clark, et al. Fas (CD95)-dependent cell-mediated immunity to Listeria monocytogenes. Infect Immun 1998;66:4143–4150.
   PubMed Web of Science ®Google Scholar
• LR San Mateo, MM Chua, SR Weiss, and H Shen. Perforin-mediated CTL cytolysis counteracts direct cell-cell spread of Listeria monocytogenes. J Immunol 2002;169:5202–5208.
   PubMedGoogle Scholar
• EJ Wing and SH Gregory. An updated model of cell-mediated immunity—Listeriosis: Clinical and research aspects. Allergy Asthma Proc 2000;21:209–214.
   PubMedGoogle Scholar
• VP Badovinac and JT Harty. Adaptive immunity and enhanced CD8+ T cell response to Listeria monocytogenes in the absence of perforin and IFN-gamma. J Immunol 2000;164:6444–6452.
   PubMedGoogle Scholar
• DW White and JT Harty. Perforin-deficient CD8+ T cells provide immunity to Listeria monocytogenes by a mechanism that is independent of CD95 and IFN-gamma but requires TNF-alpha. J Immunol 1998;160:898–905.
   PubMedGoogle Scholar
• TD Humphreys, A Khanolkar, VP Badovinac, and JT Harty. Generation and maintenance of Listeria-specific CD8+ T cell responses in perforin-deficient mice chronically infected with LCMV. Virology 2008;370:310–322.
   PubMedGoogle Scholar
• GE Sale. Perforin in GVHD. Am J Clin Pathol 1995;104:705–706.
   PubMedGoogle Scholar
• L Marks, NH Altman, ER Podack, and RB Levy. Donor T cells lacking Fas ligand and perforin retain the capacity to induce severe GvHD in minor histocompatibility antigen mismatched bone-marrow transplantation recipients. Transplantation 2004;77:804–812.
   PubMedGoogle Scholar
• M Alsharifi, M Lobigs, J Bettadapura, Restricted Semliki Forest virus replication in perforin and Fas-ligand double-deficient mice. J Gen Virol 2008;89:1942–1944.
   PubMedGoogle Scholar
• Y Tsunetsugu-Yokota, Y Morikawa, M Isogai, Yeast-derived human immunodeficiency virus type 1 p55(gag) virus-like particles activate dendritic cells (DCs) and induce perforin expression in Gag-specific CD8(+) T cells by cross-presentation of DCs. J Virol 2003;77:10250–10259.
   PubMed Web of Science ®Google Scholar
• CT Pham and TJ Ley. The role of granzyme B cluster proteases in cell-mediated cytotoxicity. Semin Immunol 1997;9:127–133.
   PubMedGoogle Scholar
• JM McNally, CC Zarozinski, MY Lin, Attrition of bystander CD8 T cells during virus-induced T-cell and interferon responses. J Virol 2001;75:5965–5976.
   PubMed Web of Science ®Google Scholar
• DW White, A MacNeil, DH Busch, Perforin-deficient CD8+ T cells: In vivo priming and antigen-specific immunity against Listeria monocytogenes. J Immunol 1999;162:980–988.
   PubMedGoogle Scholar
• VP Badovinac, AR Tvinnereim, and JT Harty. Regulation of antigen-specific CD8+ T cell homeostasis by perforin and interferon-gamma. Science 2000;290:1354–1358.
   PubMedGoogle Scholar
• M Matloubian, M Suresh, A Glass, A role for perforin in downregulating T-cell responses during chronic viral infection. J Virol 1999;73:2527–2536.
   PubMedGoogle Scholar
• A Schildknecht, S Welti, MB Geuking, Absence of CTL responses to early viral antigens facilitates viral persistence. J Immunol 2008;180:3113– 3121.
   PubMed Web of Science ®Google Scholar
• RG Van Der Most, A Sette, C Oseroff, Analysis of cytotoxic T cell responses to dominant and subdominant epitopes during acute and chronic lymphocytic choriomeningitis virus infection. J Immunol 1996;157:5543–5554.
   PubMed Web of Science ®Google Scholar
• WJ Grossman, JW Verbsky, W Barchet, Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 2004;21:589–601.
   PubMed Web of Science ®Google Scholar
• R Clark and GM Griffiths. Lytic granules, secretory lysosomes and disease. Curr Opin Immunol 2003;15:516–521.
   PubMed Web of Science ®Google Scholar
• T Kodama, K Takeda, O Shimozato, Perforin-dependent NK cell cytotoxicity is sufficient for anti-metastatic effect of IL-12. Eur J Immunol 1999;29:1390–1396.
   PubMed Web of Science ®Google Scholar
• MJ Smyth, M Taniguchi, and SE Street. The anti-tumor activity of IL-12: Mechanisms of innate immunity that are model and dose dependent. J Immunol 2000;165:2665–2670.
   PubMed Web of Science ®Google Scholar
• CM Divino, SH Chen, W Yang, Anti-tumor immunity induced by interleukin-12 gene therapy in a metastatic model of breast cancer is mediated by natural killer cells. Breast Cancer Res Treat 2000;60:129–134.
   PubMed Web of Science ®Google Scholar
• R Hou, O Goloubeva, DS Neuberg, Interleukin-12 and interleukin-2-induced invariant natural killer T-cell cytokine secretion and perforin expression independent of T-cell receptor activation. Immunology 2003;110: 30–37.
   PubMed Web of Science ®Google Scholar
• JS Orange, J Chehimi, D Ghavimi, Decreased natural killer (NK) cell function in chronic NK cell lymphocytosis associated with decreased surface expression of CD11b. Clin Immunol 2001;99:53–64.
   PubMedGoogle Scholar
• F De Paola, R Ridolfi, A Riccobon, Restored T-cell activation mechanisms in human tumour-infiltrating lymphocytes from melanomas and colorectal carcinomas after exposure to interleukin-2. Br J Cancer 2003;88:320–326.
   PubMed Web of Science ®Google Scholar
• MJ Smyth, SE Street, and JA Trapani. Cutting edge: Granzymes A and B are not essential for perforin-mediated tumor rejection. J Immunol 2003;171:515–518.
   PubMed Web of Science ®Google Scholar
• RE Hunger, M Hristic, C Mueller, Detection of perforin and tumour necrosis factor alpha mRNA expressing cells in sclerosing lymphocytic lobulitis of the breast. J Clin Pathol 1997;50:310–313.
   PubMedGoogle Scholar
• MF Van Den Broek and H Hengartner. The role of perforin in infections and tumour surveillance. Exp Physiol 2000;85:681–685.
   PubMedGoogle Scholar
• C Lehmann, M Zeis, and L Uharek. Activation of natural killer cells with interleukin 2 (IL-2) and IL-12 increases perforin binding and subsequent lysis of tumour cells. Br J Haematol 2001;114:660–665.
   PubMed Web of Science ®Google Scholar
• S Muerkoster, MA Weigand, C Choi, Superantigen reactive Vbeta6+ T cells induce perforin/granzyme B mediated caspase-independent apoptosis in tumour cells. Br J Cancer 2002;86:828–836.
   PubMed Web of Science ®Google Scholar
• MJ Dobrzanski, JB Reome, JA Hollenbaugh, Effector cell-derived lymphotoxin alpha and Fas ligand, but not perforin, promote Tc1 and Tc2 effector cell-mediated tumor therapy in established pulmonary metastases. Cancer Res 2004;64:406–414.
   PubMedGoogle Scholar
• M Vukmanovic-Stejic, B Vyas, P Gorak-Stolinska, Human Tc1 and Tc2/Tc0 CD8 T-cell clones display distinct cell surface and functional phenotypes. Blood 2000;95:231–240.
   PubMed Web of Science ®Google Scholar
• C Traidl, S Sebastiani, C Albanesi, Disparate cytotoxic activity of nickel-specific CD8+ and CD4+ T cell subsets against keratinocytes. J Immunol 2000;165:3058–3064.
   PubMed Web of Science ®Google Scholar
• S Muralitharan, Y Wali, and AV Pathare. Perforin A91V polymorphism and putative susceptibility to hematological malignancies. Leukemia 2006;20:2178.
   PubMed Web of Science ®Google Scholar
• MJ Smyth, J Swann, JM Kelly, NKG2D recognition and perforin effector function mediate effective cytokine immunotherapy of cancer. J Exp Med 2004;200:1325–3135.
   PubMed Web of Science ®Google Scholar
• E Lavergne, B Combadiere, O Bonduelle, Fractalkine mediates natural killer-dependent antitumor responses in vivo. Cancer Res 2003;63:7468–7474.
   PubMed Web of Science ®Google Scholar
• A Barber, T Zhang, CJ Megli, Chimeric NKG2D receptor-expressing T cells as an immunotherapy for multiple myeloma. Exp Hematol 2008;36:1318– 1328.
   PubMed Web of Science ®Google Scholar
• MS Lim, SE Straus, JK Dale, Pathological findings in human autoimmune lymphoproliferative syndrome. Am J Pathol 1998;153:1541–1550.
   PubMed Web of Science ®Google Scholar
• CS Ng, ST Lo, JK Chan, and WC Chan. CD56+ putative natural killer cell lymphomas: Production of cytolytic effectors and related proteins mediating tumor cell apoptosis? Hum Pathol 1997;28:1276–1282.
   PubMed Web of Science ®Google Scholar
• RP Wallin, V Screpanti, J Michaelsson, Regulation of perforin-independent NK cell-mediated cytotoxicity. Eur J Immunol 2003;33:2727–2735.
   PubMed Web of Science ®Google Scholar
• LH Young, LB Peterson, LS Wicker, In vivo expression of perforin by CD8 +lymphocytes in autoimmune disease. Studies on spontaneous and adoptively transferred diabetes in nonobese diabetic mice. J Immunol 1989;143:3994–3999.
   PubMedGoogle Scholar
• HT Kreuwel, DJ Morgan, T Krahl, Comparing the relative role of perforin/granzyme versus Fas/Fas ligand cytotoxic pathways in CD8+ T cell-mediated insulin-dependent diabetes mellitus. J Immunol 1999;163:4335–4341.
   PubMedGoogle Scholar
• H Iwahashi, N Itoh, K Yamagata, Molecular mechanisms of pancreatic beta-cell destruction in autoimmune diabetes: Potential targets for preventive therapy. Cytokines Cell Mol Ther 1998;4:45–51.
   PubMedGoogle Scholar
• X Su, Q Hu, JM Kristan, Significant role for Fas in the pathogenesis of autoimmune diabetes. J Immunol 2000;164:2523–2532.
   PubMed Web of Science ®Google Scholar
• I Apostolou, Z Hao, K Rajewsky, and H von Boehmer. Effective destruction of Fas-deficient insulin-producing beta cells in type 1 diabetes. J Exp Med 2003;198:1103–1106.
   PubMed Web of Science ®Google Scholar
• JW Yoon and HS Jun. Cellular and molecular pathogenic mechanisms of insulin-dependent diabetes mellitus. Ann N Y Acad Sci 2001;928:200–211.
   PubMed Web of Science ®Google Scholar
• S Seewaldt, HE Thomas, M Ejrnaes, Virus-induced autoimmune diabetes: Most beta-cells die through inflammatory cytokines and not perforin from autoreactive (anti-viral) cytotoxic T-lymphocytes. Diabetes 2000;49:1801–1809.
   PubMedGoogle Scholar
• B Balasa, K Van Gunst, N Jung, Islet-specific expression of IL-10 promotes diabetes in nonobese diabetic mice independent of Fas, perforin, TNF receptor-1, and TNF receptor-2 molecules. J Immunol 2000;165:2841–2849.
   PubMedGoogle Scholar
• PL Herrera, DM Harlan, and P Vassalli. A mouse CD8 T cell-mediated acute autoimmune diabetes independent of the perforin and Fas cytotoxic pathways: Possible role of membrane TNF. Proc Natl Acad Sci U S A 2000;97:279–284.
   PubMed Web of Science ®Google Scholar
• J Allison, H Thomas, D Beck, Transgenic overexpression of human Bcl-2 in islet beta cells inhibits apoptosis but does not prevent autoimmune destruction. Int Immunol 2000;12:9–17.
   PubMedGoogle Scholar
• VK Chiu, CM Walsh, CC Liu, Bcl-2 blocks degranulation but not fas-based cell-mediated cytotoxicity. J Immunol 1995;154:2023–2032.
   PubMed Web of Science ®Google Scholar
• RK Lee, J Spielman, and ER Podack. Bcl-2 protects against Fas-based but not perforin-based T cell-mediated cytolysis. Int Immunol 1996;8:991–1000.
   PubMed Web of Science ®Google Scholar
• YS Kap, P Smith, SA Jagessar, Fast progression of recombinant human myelin/oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis in marmosets is associated with the activation of MOG34–56-specific cytotoxic T cells. J Immunol 2008;180:1326–1337.
   PubMedGoogle Scholar
• B Zhang, T Yamamura, T Kondo, Regulation of experimental autoimmune encephalomyelitis by natural killer (NK) cells. J Exp Med 1997;186:1677–1687.
   PubMed Web of Science ®Google Scholar
• C Schmaltz, O Alpdogan, BJ Kappel, T cells require TRAIL for optimal graft-versus-tumor activity. Nat Med 2002;8:1433–1437.
   PubMed Web of Science ®Google Scholar
• V Snell, K Clodi, S Zhao, Activity of TNF-related apoptosis-inducing ligand (TRAIL) in haematological malignancies. Br J Haematol 1997;99:618–624.
   PubMed Web of Science ®Google Scholar
• C Brander, UB Matter-Reissmann, NG Jones, Inhibition of human NK cell-mediated cytotoxicity by exposure to ammonium chloride. J Immunol Methods 2001;252:1–14.
   PubMedGoogle Scholar
• MA Taylor, B Ward, JD Schatzle, and M Bennett. Perforin- and Fas-dependent mechanisms of natural killer cell-mediated rejection of incompatible bone marrow cell grafts. Eur J Immunol 2002;32:793–799.
   PubMedGoogle Scholar
• D Kagi, P Seiler, J Pavlovic, The roles of perforin- and Fas-dependent cytotoxicity in protection against cytopathic and noncytopathic viruses. Eur J Immunol 1995;25:3256–3262.
   PubMedGoogle Scholar
• A Yoshimi, I Tsuge, H Namizaki, Epstein-Barr virus-specific T-cell cytotoxicity is mediated through the perforin pathway in patients with lymphoproliferative disorders after allogeneic bone marrow transplantation. Br J Haematol 2002;116:710–715.
   PubMedGoogle Scholar
• A Khanolkar, H Yagita, and MJ Cannon. Preferential utilization of the perforin/granzyme pathway for lysis of Epstein-Barr virus-transformed lymphoblastoid cells by virus-specific CD4+ T cells. Virology 2001;287:79–88.
   PubMedGoogle Scholar
• K Ohshima, J Suzumiya, M Sugihara, et al. CD95 (Fas) ligand expression of Epstein-Barr virus (EBV)-infected lymphocytes: A possible mechanism of immune evasion in chronic active EBV infection. Pathol Int 1999;49:9–13.
   PubMed Web of Science ®Google Scholar
• B Samten, B Wizel, H Shams, CD40 ligand trimer enhances the response of CD8+ T cells to Mycobacterium tuberculosis. J Immunol 2003;170:3180–3186.
   PubMedGoogle Scholar
• SS De La Barrera, M Finiasz, A Frias, Specific lytic activity against mycobacterial antigens is inversely correlated with the severity of tuberculosis. Clin Exp Immunol 2003;132:450–461.
   PubMedGoogle Scholar
• P Zhou, BL Freidag, CC Caldwell, and RA Seder. Perforin is required for primary immunity to Histoplasma capsulatum. J Immunol 2001;166:1968– 1974.
   PubMedGoogle Scholar
• A Henriques-Pons, GM Oliveira, MM Paiva, Evidence for a perforin-mediated mechanism controlling cardiac inflammation in Trypanosoma cruzi infection. Int J Exp Pathol 2002;83:67–79.
   PubMed Web of Science ®Google Scholar
• U Muller, V Sobek, S Balkow, Concerted action of perforin and granzymes is critical for the elimination of Trypanosoma cruzi from mouse tissues, but prevention of early host death is in addition dependent on the FasL/Fas pathway. Eur J Immunol 2003;33:70–78.
   PubMed Web of Science ®Google Scholar
• I Voskoboinik and JA Trapani. Addressing the mysteries of perforin function. Immunol Cell Biol 2006;84:66–71.
   PubMedGoogle Scholar
• M Sarwal, MS Chua, N Kambham, Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. N Engl J Med 2003;349:125–138.
   PubMed Web of Science ®Google Scholar
• MM Sarwal, A Jani, S Chang, Granulysin expression is a marker for acute rejection and steroid resistance in human renal transplantation. Hum Immunol 2001;62:21–31.
   PubMed Web of Science ®Google Scholar
• VK Sharma, RM Bologa, B Li, Molecular executors of cell death—Differential intrarenal expression of Fas ligand, Fas, granzyme B, and perforin during acute and/or chronic rejection of human renal allografts. Transplantation 1996;62:1860–1866.
   PubMedGoogle Scholar
• C Clayberger. Cytolytic molecules in rejection. Curr Opin Organ Transplant 2009;14:30–33.
   PubMedGoogle Scholar
• J Chia, KP Yeo, JC Whisstock, Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer. Proc Natl Acad Sci U S A Epub 2009 June 1; 106:9809–9814.
   Google Scholar