A NOVEL CYTOTOXICITY OF CD4+ TH1 CLONES ON HEAT-SHOCKED TUMOR TARGETS .1. IMPLICATIONS FOR INTERNAL DISINTEGRATION MODEL FOR TARGET DEATH AND HYPERTHERMIA TREATMENT OF CANCERS

Abstract

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.