TY - JOUR
T1 - bcl-2 protects against Fas-based but not perforin-based T cell-mediated cytolysis
AU - Lee, Richard K.
AU - Spielman, Julie
AU - Podack, Eckhard R.
N1 - Funding Information:
We thank Drs David Kagi, Andreas Strasser and Hans Hengartner for helpful discussions and comments on the manuscript We are grateful to Gina Miragliotta, Kristin J. Olsen, J. Fred Rhoderick and Dong Yan Zhao for expert assistance. R. K L is supported by a Physician Scientist Program Fellowship from the University of Miami School of Medicine. This work is supported by National Institutes of Health grants CA-39201 and CA-57904 toE R P
PY - 1996
Y1 - 1996
N2 - Fas ligand and perforin are the two key effector mechanisms in T cell-mediated cytotoxicity. These molecules mediate cytolysis of target cells by membrane damage and apoptosis. bcl-2 is known to protect cells against apoptosis induced by many stimuli including growth factor removal. However bcl-2's effect on Fas ligand and perforin-induced lysis has not been studied extensively. We investigated the effect of overexpression of bcl-2 alone, Fas alone or their combined overexpression on lysis of a commonly used target, P815, by perforin-sufficient, Fas ligand-sufficient and perforin-deficient or Fas ligand-deficient, allospecific cytotoxic T lymphocytes (CTL). Wild-type P815 are susceptible to lysis by perforin-sufficient CTL, regardless of the presence or absence (gld) of Fas ligand, but are poorly lysed by perforin-deficient CTL. Fas transfection of P815 makes target cells highly susceptible to lysis by both perforin-sufficient and -deficient CTL, indicating the presence of the Fas ligand-mediated cytotoxicity on both types of CTL. Co-transfection of P815-fas with bcl-2 abolishes their increased susceptibility to Fas-mediated lysis, even in the face of Fas overexpression on the cell membrane. The protective effect of bcl-2 against cell lysis is evident with perforin-deficient CTL as effector cells or when perforin activity is eliminated by the absence of extracellular calcium in perforin-sufficient CTL. bcl-2 overexpression by P815, however, does not protect against CTL lysis by the perforin pathway, regardless of Fas overexpression, as demonstrated by Fas ligand mutated gld and wild-type perforin-sufficient CTL. Therefore bcl-2 can protect P815 target cells against Fas-mediated lysis when triggered by the Fas ligand on CTL, but not against perforin-mediated lysis.
AB - Fas ligand and perforin are the two key effector mechanisms in T cell-mediated cytotoxicity. These molecules mediate cytolysis of target cells by membrane damage and apoptosis. bcl-2 is known to protect cells against apoptosis induced by many stimuli including growth factor removal. However bcl-2's effect on Fas ligand and perforin-induced lysis has not been studied extensively. We investigated the effect of overexpression of bcl-2 alone, Fas alone or their combined overexpression on lysis of a commonly used target, P815, by perforin-sufficient, Fas ligand-sufficient and perforin-deficient or Fas ligand-deficient, allospecific cytotoxic T lymphocytes (CTL). Wild-type P815 are susceptible to lysis by perforin-sufficient CTL, regardless of the presence or absence (gld) of Fas ligand, but are poorly lysed by perforin-deficient CTL. Fas transfection of P815 makes target cells highly susceptible to lysis by both perforin-sufficient and -deficient CTL, indicating the presence of the Fas ligand-mediated cytotoxicity on both types of CTL. Co-transfection of P815-fas with bcl-2 abolishes their increased susceptibility to Fas-mediated lysis, even in the face of Fas overexpression on the cell membrane. The protective effect of bcl-2 against cell lysis is evident with perforin-deficient CTL as effector cells or when perforin activity is eliminated by the absence of extracellular calcium in perforin-sufficient CTL. bcl-2 overexpression by P815, however, does not protect against CTL lysis by the perforin pathway, regardless of Fas overexpression, as demonstrated by Fas ligand mutated gld and wild-type perforin-sufficient CTL. Therefore bcl-2 can protect P815 target cells against Fas-mediated lysis when triggered by the Fas ligand on CTL, but not against perforin-mediated lysis.
KW - CD8
KW - Cytotoxicity
KW - Fas ligand
KW - gld
KW - T lymphocyte
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U2 - 10.1093/intimm/8.7.991
DO - 10.1093/intimm/8.7.991
M3 - Article
C2 - 8757944
AN - SCOPUS:0030037138
VL - 8
SP - 991
EP - 1000
JO - International Immunology
JF - International Immunology
SN - 0953-8178
IS - 7
ER -