CD95 ligand-expressing tumors are rejected in anti-tumor TCR transgenic perforin knockout mice.
CD95 (APO-/Fas) ligand (CD95L) is a member of the TNF family predominantly expressed by activated T and NK cells but also by tumors of diverse cellular origin. CD95L trimerizes surface CD95 expressed by target cells that subsequently undergo apoptosis. The role of the CD95/CD95L system in the down-regulation of an immune response (activation-induced cell death) is established. However, it is so far unclear why tumors express CD95L. To investigate whether tumors use the CD95L to down-regulate an anti-tumor immune response, we established a transgenic (tg) mouse model consisting of 1) apoptosis-resistant tumor cells, designated LKC-CD95L, which express functional CD95L and the model tumor Ag K(b); and 2) perforin knockout (PKO) anti-K(b) TCR tg mice. L1210-Fas antisense expressing K(b), crmA, and CD95L (LKC-CD95L) killed CD95(+) unrelated tumor targets and Con A-activated splenocytes from anti-K(b) TCR tg PKO mice by a CD95L-dependent mechanism in vitro. However, we could not detect any cytotoxic activity against anti-tumor (anti-K(b)) T cells in vivo. We also observed reduced growth of LKC-CD95L in nude mice and rapid rejection in anti-K(b) TCR tg PKO mice. Because the tumor cells are resistant to CD95L-, TNF-alpha-, and TNF-related apoptosis-inducing ligand-induced apoptosis and the mice used are perforin-deficient, the involvement of these four cytotoxicity mechanisms in tumor rejection can be excluded. The histological examination of tumors grown in nude mice showed infiltration of LKC-CD95L tumors by neutrophils, whereas L1210-Fas antisense expressing K(b) and crmA (LKC) tumor tissue was neutrophil-free. Chemotaxis experiments revealed that CD95L has no direct neutrophil-attractive activity. Therefore, we conclude that LKC-CD95L cells used an indirect mechanism to attract neutrophils that may cause tumor rejection.
Behrens
C K
CK
Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.
Igney
F H
FH
Arnold
B
B
Möller
P
P
Krammer
P H
PH
D000818:Animals; D019556:COS Cells; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002630:Chemotactic Factors / Q000502:physiology; D053222:Fas Ligand Protein; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology*; D006183:H-2 Antigens / Q000235:genetics; D007939:Leukemia L1210 / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D008024:Ligands; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000276:immunology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D015843:Serpins / Q000235:genetics; D012995:Solubility; D014162:Transfection; D019076:Transgenes / Q000276:immunology*; D014764:Viral Proteins; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
D002630:Chemotactic Factors; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D016376:Oligonucleotides, Antisense; D052899:Pore Forming Cytotoxic Proteins; D011948:Receptors, Antigen, T-Cell; D015843:Serpins; D014764:Viral Proteins; D019014:fas Receptor; D054353:Perforin; C074641:interleukin-1beta-converting enzyme inhibitor