Metallothionein-induced suppression of cytotoxic T lymphocyte function: an important immunoregulatory control

Exposure to environmental toxicants can alter a variety of cellular functions that are critical to immune function. Cellular responses to these changes include increased synthesis of a number of stress proteins, some of which have been shown to have immunomodulatory capacity. One of these stress proteins, metallothionein (MT) is a low molecular weight, cysteine-rich protein that can be induced by exposure to environmental stressors as well as many inflammatory and tumorigenic agents. As a consequence, high levels of MT have been found at sites of inflammation and in certain types of neoplastic cells. In light of the suppressive effects that MT has been found to have on T-dependent humoral immunity, we investigated the potential role that MT might play in cell-mediated immune functions that could contribute to antitumor immunity. We found that MT can cause dramatic decreases in murine cytotoxic T lymphocyte (CTL) activity against allogeneic target cells. MT also reduces the proliferative response of CTLL-2 cells to cytokines, and decreases the level of major histocompatibility complex (MHC) Class I and CD8 molecules detectable on the surface of lymphocytes, while having no significant effect on the level of CD4. These findings suggest that the immunosuppressive effects of MT may at least in part reflect interference with cell-cell interactions that are ordinarily critical to cell-mediated immunity. Despite this suppressive effect on CTL functioning, MT was found to augment mixed lymphocyte reactions (MLRs) in concert with increased interleukin-2 receptor (IL-2R) expression. This MT-augmented proliferation was observed in both allogeneic and syngeneic MLR. Taken together, these results indicate that MT may increase the number of immature T cells, but decrease their differentiation to the effector CTL stage. These effects of extracellular MT on T-cell function may contribute to the immunosuppression of cell-mediated immunity that has been ascribed to inducers of MT synthesis. In addition, they may point to the manipulation of MT levels as a means of reducing the undesirable immunomodulatory effects of these agents.