Acute rejection of allografted CTL-susceptible leukemia cells from perforin/Fas ligand double-deficient mice.
The generation of knockout mice demonstrated that CD4(+), but not CD8(+), T cells were essential for the rejection of allografted skin or heart, presumably because these targets were CTL resistant. In the case of CTL-susceptible targets (e.g., P815 mastocytoma cells and EL-4 or RLmale1 T lymphoma cells), however, it is assumed that the CTL is the effector cell responsible for allograft rejection and that perforin and Fas ligand (FasL) pathways are the killing mechanisms. In the present study, we examined the role of these cytotoxic molecules in the rejection of i.p. allografted CTL-susceptible leukemia cells. Unexpectedly, the allografted leukemia cells were acutely rejected from gld (a mutation of FasL), perforin(-/-), or double-deficient mice. The peritoneal exudate cells from gld or normal mice showed T cell-, TCRalphabeta-, and perforin-dependent cytotoxic activity against the allograft, whereas the exudate cells from perforin(-/-) mice exhibited almost full cytotoxic activity in the presence of Fas-Fc. Furthermore, the infiltrates from double-deficient mice showed a high cytotoxic activity against the allografted cells even in the presence of anti-TCRalphabeta Ab or in the absence of T cells. The cytotoxic cells appeared to be macrophages, because they were Mac-1(+) mononuclear cells with a kidney- or horseshoe-shaped nucleus and because the cytotoxic activity was completely suppressed by the addition of N(G)-monomethyl-l-arginine, an inhibitor of inducible NO synthase. These results indicate that macrophages are ready and available to kill CTL-susceptible allografts when CTLs lack both perforin and FasL molecules.
Nomi
Hayahito
H
Department of Physiology, Osaka Medical College, Takatsuki, Japan.
Tashiro-Yamaji
Junko
J
Yamamoto
Yumiko
Y
Miura-Takeda
Sayako
S
Miyoshi-Higashino
Masako
M
Takahashi
Takeshi
T
Azuma
Haruhito
H
Ueda
Haruhiko
H
Katsuoka
Yoji
Y
Kubota
Takahiro
T
Yoshida
Ryotaro
R
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000172:deficiency* / Q000276:immunology; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D007938:Leukemia / Q000235:genetics / Q000276:immunology; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009368:Neoplasm Transplantation / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000276:immunology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000172:deficiency* / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology*; D014184:Transplantation, Homologous; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; D016177:Macrophage-1 Antigen; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D054353:Perforin; D019323:omega-N-Methylarginine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse