CD95 ligand-expressing tumors are rejected in anti-tumor TCR transgenic perforin knockout mice.

Abstract

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.

• Authors: C K Behrens, F H Igney, B Arnold, P Möller, P H Krammer
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 166 Issue 5 Pg. 3240-7 (Mar 01 2001) ISSN: 0022-1767 [Print] United States
• PMID: 11207278 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemotactic Factors
• Fas Ligand Protein
• Fasl protein, mouse
• H-2 Antigens
• H-2Kb protein, mouse
• Ligands
• Membrane Glycoproteins
• Oligonucleotides, Antisense
• Pore Forming Cytotoxic Proteins
• Receptors, Antigen, T-Cell
• Serpins
• Viral Proteins
• fas Receptor
• Perforin
• interleukin-1beta-converting enzyme inhibitor

Topics

• Animals
• COS Cells
• Cell Division (genetics, immunology)
• Chemotactic Factors (physiology)
• Fas Ligand Protein
• Graft Rejection (genetics, immunology)
• H-2 Antigens (genetics)
• Leukemia L1210 (genetics, immunology, pathology, prevention & control)
• Ligands
• Membrane Glycoproteins (biosynthesis, deficiency, genetics, physiology)
• Mice
• Mice, Inbred DBA
• Mice, Knockout
• Mice, Nude
• Mice, Transgenic
• Neoplasm Transplantation
• Oligonucleotides, Antisense (genetics, immunology)
• Perforin
• Pore Forming Cytotoxic Proteins
• Receptors, Antigen, T-Cell (genetics)
• Serpins (genetics)
• Solubility
• Transfection
• Transgenes (immunology)
• Viral Proteins
• fas Receptor (genetics, metabolism)