A novel cytotoxicity of CD4+ Th1 clones on heat-shocked tumor targets. I. Implications for internal disintegration model for target death and hyperthermia treatment of cancers.
A novel cytotoxicity, which is normally hidden but unveiled upon interacting with heat-shocked tumor target, has been identified in CD4+ Th1 cells. When TNF-resistant, Ag-presenting tumor targets were heat shocked, the cytotoxicity by specific Th1 clones was significantly enhanced. Interestingly, the DNA of heat-shocked, unpulsed targets including Ia- tumor cells were also fragmented by Th1 clones. In contrast to the Ag-dependent, MHC-restricted cytotoxicity, the heat-shock-induced sensitivity to Th1 clones was a) Ag independent and MHC unrestricted, b) insensitive to CD4-mAb, c) resistant to actinomycin D and cycloheximide, and d) greatly enhanced by cholera toxin, PGE1, PGE2, and dibutyryl cAMP. This novel cytotoxicity was inhibited by mAb specific to lymphocyte function-associated Ag-1 and intercellular adhesion molecule-1. Upon culturing at 37 degrees C, mildly heat-shocked target cells gradually recovered, indicating that the heat-shock-induced sensitivity was transient and reversible. The implication of this study for a signal-induced internal disintegration mechanism for target death is discussed. The novel cytotoxicity of CD4+ Th1 cells may be an important mechanism of immune regulation under febrile conditions and an underlying mechanism for the hyperthermia treatment of cancers.
Ozdemirli
M
M
Department of Pathology, Boston University School of Medicine, MA 02118.
Akdeniz
H
H
el-Khatib
M
M
Ju
S T
ST
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology; D002999:Clone Cells; D000242:Cyclic AMP / Q000502:physiology; D003602:Cytotoxicity, Immunologic; D004249:DNA Damage; D004734:Energy Metabolism; D006358:Hot Temperature; D007111:Immunity, Cellular; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014407:Tumor Cells, Cultured / Q000276:immunology*
D000951:Antigens, Neoplasm; D016827:CD8 Antigens; D011948:Receptors, Antigen, T-Cell; D000242:Cyclic AMP