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*
Institute of Biochemistry, University of Lausanne, BIL Research Center, Epalinges, Switzerland;
Parke-Davis Research Institute, Paris, France; and
Institute of Molecular Medicine, Medical College of Georgia, Augusta, GA
T cell activation by the specific Ag results in dramatic changes of
the T cell phenotype that include a rapid and profound down-regulation
and degradation of triggered TCRs. In this work, we investigated the
fate of the TCR-associated ZAP-70 kinase in Ag-stimulated T cells. T
cells stimulated by peptide-pulsed APCs undergo an Ag dose-dependent
decrease of the total cellular content of ZAP-70, as detected by FACS
analysis and confocal microscopy on fixed and permeabilized T cell-APC
conjugates and by Western blot on total cell lysates. The time course
of ZAP-70 consumption overlaps with that of 
-chain degradation,
indicating that ZAP-70 is degraded in parallel with TCR internalization
and degradation. Pharmacological activation of protein kinase C (PKC)
does not induce ZAP-70 degradation, which, on the contrary, requires
activation of protein tyrosine kinases. Two lines of evidence indicate
that the Ca2+-dependent cysteine protease calpain plays a
major role in initiating ZAP-70 degradation: 1) treatment of T cells
with cell-permeating inhibitors of calpain markedly reduces ZAP-70
degradation; 2) ZAP-70 is cleaved in vitro by calpain. Our results show
that, in the course of T cell-APC cognate interaction, ZAP-70 is
rapidly degraded via a calpain-dependent
mechanism.
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