Ca2+-dependent, Fas- and perforin-independent apoptotic death of allografted tumor cells by a type of activated macrophage.
Both perforin- and Fas ligand (FasL)-deficient CTLs show impaired lytic activity toward most target cells. In this study, we examined whether these molecules could be involved in the cell-to-cell contact-dependent cytotoxicity mediated by macrophages infiltrating into the rejection site of allografted Meth A fibrosarcoma cells. FasL-expressing lymph node cells from MRL-lpr/lpr mice were inactive toward Meth A tumor cells. In C3H/HeJ-gld/gld (abnormal FasL) mice, allograft-induced macrophages (AIM) were cytotoxic against Meth A cells expressing no Fas Ag. Furthermore, allografted Meth A tumor cells were acutely rejected by both C3H/HeJ-gld/gld and control C3H/HeJ mice, indicating that the cytotoxic activity of AIM against Meth A tumor cells was Fas/FasL independent. On the other hand, the cytotoxic activity of AIM against the allografts was dose dependently inhibited by EGTA; and the suppression was restored by the addition of Ca2+, but not Mg2+, implying the involvement of perforin in the cytotoxicity. In the perforin-deficient mice, however, AIM were cytotoxic against Meth A tumor cells; and allografted Meth A tumor cells were acutely rejected by both perforin-deficient and control B6 mice, indicating a perforin-independent cytotoxicity. Thus, through a yet unknown mechanism, AIM induced the apoptotic death of allografted Meth A tumor cells. These results indicate that AIM-mediated cytotoxicity against allografted Meth A tumor cells is Ca2+ dependent, and that an attack by AIM results in the apoptotic death of allografted Meth A tumor cells through a third mechanism, one other than the Fas/FasL- and perforin-based pathways.
Yoshida
R
R
Department of Cell Biology, Osaka Bioscience Institute, Suita, Japan.
Sanchez-Bueno
A
A
Yamamoto
N
N
Einaga-Naito
K
K
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002118:Calcium / Q000276:immunology*; D002450:Cell Communication; D053222:Fas Ligand Protein; D005354:Fibrosarcoma / Q000276:immunology / Q000473:pathology*; D007111:Immunity, Cellular; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D014184:Transplantation, Homologous
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D002118:Calcium