Blood, Vol. 95 No. 9 (May 1), 2000:
pp. 2733-2741
PLENARY PAPER
Potentiation of CD3-induced expression of the linker for
activation of T cells (LAT) by the calcineurin inhibitors cyclosporin A
and FK506
David Peters,
Masahiro Tsuchida,
Eric R. Manthei,
Tausif Alam,
Clifford S. Cho,
Stuart J. Knechtle, and
Majed M. Hamawy
From the Department of Surgery, Division of Transplantation,
University of Wisconsin, Madison, WI.
The activation of blood cells, including T cells, triggers
intracellular signals that control the expression of critical
molecules, including cytokines and cytokine receptors. We show that
T-cell receptor (TCR) ligation increases the cellular level of the
protein linker for activation of T cells (LAT), a molecule critical for T-cell development and function. T-cell activation increased LAT messenger RNA, as determined by reverse transcription-polymerase chain
reaction and by Northern blotting. The TCR-induced increase in LAT
expression involved the activation of the serine/threonine kinases PKC
and MEK, because inhibitors of these kinases blocked the increase in
LAT. Accordingly, the PKC activator phorbol myristate acetate
up-regulated LAT expression. Strikingly, the calcineurin inhibitors
cyclosporin A (CsA) and FK506 strongly potentiated TCR-induced LAT
expression, suggesting that the activation of calcineurin following TCR
ligation negatively regulates LAT expression. Accordingly,
Ca++ ionophores, which can activate calcineurin by
increasing intracellular Ca++, blocked the TCR-induced
increase in cellular LAT. CsA and FK506 blocked the Ca++
ionophores' inhibitory effect on LAT expression. Notably, CsA and FK506 preferentially up-regulated TCR-induced LAT expression; under
the same conditions, these compounds did not increase the expression of
14 other molecules that previously had been implicated in T-cell
activation. These data show that TCR-induced LAT expression involves
the activation of the PKC-Erk pathway and is negatively regulated by
the activation of calcineurin. Furthermore, the potentiation of
TCR-induced LAT expression by CsA and FK506 suggests that the action of
these agents involves up-regulating the cellular level of critical
signaling molecules. These findings may have important therapeutic implications.
