Glutathione Reverses the Inhibition of T Cell Responses by Superoptimal Numbers of "Nonprofessional" Antigen Presenting Cells

"Professional" antigen-presenting cells (APC) such as macrophages or dendritic cells display not only antigens to specific T cell receptors but deliver in addition certain "costimulatory signals." Macrophages also release substantial amounts of cysteine and raise thereby the intracellular glutathione (GSH) levels of activated T cells in their vicinity. We therefore studied the hypothesis that stimulation with "nonprofessional" APC that fail to deliver cysteine may induce a type of immunological unresponsiveness that is caused by GSH deficiency and prevented by administration of exogenous GSH. Our experiments showed that cytotoxic T cell (CTL) responses are indeed strongly suppressed in vivo and in vitro by different types of nonprofessional APC and reconstituted by administration of GSH at the time of immunization if these APC are administered at relatively high doses. At lower doses, however, the same cell types may stimulate CTL responses without exogenous GSH, and the responses may be even inhibited in these cases by GSH. CTL responses were not suppressed by high numbers of professional APC, and GSH had no substantial effect on CTL responses after in vivo immunization with professional APC or a cysteine-releasing tumor variant. However, exogenous GSH reconstituted the otherwise weak CTL response in vitro against splenic adherent cells from athymic (nude) mice. Experiments with cloned T cells (D10.G4.1) finally showed that stimulation with graded concentrations of mitogen causes a dose-dependent decrease of intracellular GSH levels. These effects are expected to play a role in "high zone tolerance," in CTL responses against certain types of tumors, and in pathological conditions with a GSH deficiency.