Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
Unrestricted cytotoxicity of murine CD4 Th1 lymphocytes on heat-shocked tumor targets.
Diss Abstr Int [B]; 54(8):4091 1994. Unique Identifier : AIDSLINE ICDB/95606420 Ozdemirli M; Boston Univ.
Abstract:
Murine cytotoxic CD4 Th1 lymphocytes express a cell contact-dependent cytotoxicity that induces target apoptosis. This cytotoxic process was resolved into three stages comparable with those of CD8 CTL: conjugate formation/activation, lethal hit, and effector-independent target lysis. Upon activation, CD4 Th1 clones synthesized a short-lived cytotoxic machinery that delivered a short-ranged and quick-acting lethal hit to target cells in an extracellular Ca++-independent manner and induced a program for DNA fragmentation and 51Cr-release. Heat-shock treatment of target cells was used hoping that some signals for target death would be bypassed whereas other signals would remain dependent on effector/target interaction. It was observed that heat-shock enhanced the susceptibility of antigen-presenting target cells to Th1 cells. Moreover, heat-shocked targets were also killed by a novel cytotoxicity of Th1 cells. In contrast to antigen-specific cytotoxicity, this cytotoxicity was major histocompatibility complex (MHC) class II-unrestricted, insensitive to CD4-monoclonal antibody (mAb) and Ia-mAb, and was enhanced by cAMP-inducing agents. Moreover, it was not dependent on extracellular Ca2+, protein kinase C-activation, and de novo mRNA and protein synthesis. However, similar to antigen-specific cytotoxicity, this cytotoxicity was inhibited by LFA-1-mAb and ICAM-1-mAb. Freshly prepared CD4 and CD8 CTL from mixed lymphocyte reactions, and two CD8 CTL clones also expressed this MHC-unrestricted cytotoxicity on heat-shocked tumor cells. Two CD4 Th2 clones and two CD4 Th1 clones that were not cytotoxic to antigen-specific targets lacked the cytotoxicity on heat-shocked targets. Heat-shock proteins (hsp) were not involved, because (a) there was no increase in conjugate formation, (b) other stress treatments of targets which induced hsp did not induce cytotoxicity by Th1 cells, and (c) hsp expression in heat-shocked targets did not correlate with susceptibility to killing. This study demonstrates a constitutively expressed cytotoxic signal in cytotoxic T cells, which causes apoptosis of heat-shocked tumor targets. This implies that heat-shocked tumor targets may be eliminated by T cells in patients undergoing hyperthermia treatment, thus providing an underlying mechanism for hyperthermia treatment of cancers. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD94-04446)
Keywords: Animal Apoptosis *Cytotoxicity, Immunologic CD4-Positive T-Lymphocytes/IMMUNOLOGY CD8-Positive T-Lymphocytes/IMMUNOLOGY Heat-Shock Proteins/*PHARMACOLOGY Histocompatibility Antigens Class II Mice T-Lymphocytes, Cytotoxic/IMMUNOLOGY Th1 Cells/*IMMUNOLOGY Tumor Cells, Cultured THESIS 950430
M9541144
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Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
