Adoptive transfer: the role of perforin in mouse cytotoxic T lymphocyte rejection of human tumor xenografts in vivo.
The popliteal lymph node cells of immunocompetent mice generated a strong in vitro cytotoxic response to footpad injection of several human tumor cell lines and the resulting mouse effector cells predominantly used a perforin-mediated cytotoxic mechanism. A relatively minor FasL-dependent cytotoxic response to CEM-CCRF and Jurkat leukemias, but not colon carcinoma COLO 205 cells, was also detected in immunized perforin-deficient mice. In vitro depletion of CD3+ CD8+ T cells, but not CD4+ T or NK1.1+ cells, completely inhibited lysis of human tumor cells, suggesting that CD3+ CD8+ T cells were effectors of perforin-mediated xenospecific cytotoxicity. Xenospecific cytotoxic T cells from wild-type mice were extremely efficient at rejecting tumor when adoptively transferred into scid mice bearing established COLO 205, CEM-CCRF, or Jurkat tumor xenografts. By contrast, cytotoxic T lymphocytes of perforin-deficient mice had no effect on the growth of established tumor xenografts. These data indicate that perforin, and hence direct cytotoxicity, plays a key role in the ability of adoptively transferred CD8+ cytotoxic T lymphocytes to eradicate established xenografts.
Smyth
M J
MJ
Cellular Cytotoxicity Laboratory, The Austin Research Institute, Heidelberg, Victoria, Australia. mj_smyth@muwayf.unimelb.edu.au
Kershaw
M H
MH
Darcy
P K
PK
Trapani
J A
JA
D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D005260:Female; D006084:Graft Rejection / Q000209:etiology* / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014183:Transplantation, Heterologous / Q000276:immunology*; D014407:Tumor Cells, Cultured
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin