T cell-mediated, IFN-gamma-facilitated rejection of murine B16 melanomas.
The murine melanoma cell line B16.F10 (H-2b) was used to study specific T cell responses that reject tumors. Stable B16 transfectants were established that express viral Ags, either the hepatitis B surface Ag (HBsAg) or the large tumor Ag (T-Ag) of SV40. B16 cells and their transfected sublines were CD40+ CD44+ but expressed no (or low levels of the) costimulator molecules CD154 (CD40L), CD48, CD54, CD80, and CD86. Surface expression of MHC class I (Kb, Db) and class II (I-Ab) molecules by B16 cells was low, but strikingly up-regulated by IFN-gamma. CD95 (Fas) and CD95 ligand (CD95L (FasL)) were "spontaneously" expressed by B16 cells growing in vitro in serum-free medium; these markers were strikingly up-regulated by IFN-gamma. B16 cells coexpressing CD95 and CD95L were irreversibly programmed for apoptosis. In vitro, noninduced B16 transfectants stimulated a specific IFN-gamma release response, but no cytolytic response (in a 4-h assay) in MHC class I-restricted CTL; in contrast, IFN-gamma-induced B16 targets were efficiently and specifically lysed by CTL. In vivo, B16 transfectants were specifically rejected by DNA-vaccinated syngeneic hosts through a T-dependent immune effector mechanism. The tumors showed evidence of massive apoptosis in vivo during the rejection process. The data suggest that CTL-derived IFN-gamma enhances an intrinsic suicide mechanism of these tumor cells in addition to facilitating lytic interactions of effectors with tumor targets.
Institute of Medical Microbiology, University of Ulm, Germany.
W
W
Böhm
S
S
Thoma
F
F
Leithäuser
P
P
Möller
R
R
Schirmbeck
J
J
Reimann
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000096:biosynthesis; D017209:Apoptosis / Q000276:immunology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D006514:Hepatitis B Surface Antigens / Q000096:biosynthesis; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000502:physiology*; D008024:Ligands; D008297:Male; D008546:Melanoma, Experimental / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D013539:Simian virus 40 / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014162:Transfection / Q000276:immunology; D014185:Transplantation, Isogeneic; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000096:biosynthesis
D000952:Antigens, Polyomavirus Transforming; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006514:Hepatitis B Surface Antigens; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor; D007371:Interferon-gamma