Toxicological Sciences, Vol 52, 199-208, Copyright © 1999 by Society of Toxicology
J Youn and MA Lynes
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.
ARTICLES
Metallothionein-induced suppression of cytotoxic T lymphocyte function: an important immunoregulatory control
Department of Molecular and Cell Biology, University of Connecticut, Storrs 06269, USA.
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