Expression of increased immunogenicity by thiol-releasing tumor variants.
Even moderate variations of the extracellular cysteine concentration were previously shown to affect T cell functions in vitro despite high concentrations of cystine. We therefore analyzed the membrane transport activities of T cells for cysteine and cystine, and the role of low molecular weight thiol in T cell-mediated host responses against a T cell tumor in vivo. A series of T cell clones and tumors including the highly malignant lymphoma L5178Y ESb and its strongly immunogenic variant ESb-D was found to express extremely weak transport activity for cystine but strong transport activity for cysteine. However, not all cells showed the expected requirement for cysteine (or 2-mercaptoethanol (2-ME)) in the culture medium. One group of clones and tumors including the malignant ESb-lymphoma did not respond to changes of extracellular cystine concentrations and was strongly thiol dependent. This group released only little acid soluble thiol (cysteine) if grown in cystine-containing cultures. The other T cell lines, in contrast, were able to maintain high intracellular GSH levels and DNA synthesis activity in cystine-containing culture medium without cystein or 2-ME and released substantial amounts of thiol. This group included the immunogenic ESb-D line. Additional thiol-releasing ESb variants were obtained by culturing large numbers of L5178Y ESb tumor cells in cultures without cysteine or 2-ME. All of these ESb variants showed a significantly decreased tumorigenicity and some of them induced cytotoxic and protective host responses even against the malignant ESb parent tumor. Taken together, our experiments suggest that the host response against a tumor may be limited in certain cases by the failure of the stimulator (i.e., the tumor) cell to deliver sufficient amounts of cysteine to the responding T cells.
Lim
J S
JS
Division of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Eck
H P
HP
Gmünder
H
H
Dröge
W
W
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000276:immunology; D002999:Clone Cells / Q000276:immunology; D003545:Cysteine / Q000378:metabolism*; D003553:Cystine / Q000378:metabolism; D005978:Glutathione / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D016399:Lymphoma, T-Cell / Q000276:immunology*; D008623:Mercaptoethanol / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000596:Amino Acids; D013438:Sulfhydryl Compounds; D003553:Cystine; D008623:Mercaptoethanol; D005978:Glutathione; D003545:Cysteine