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* Laboratoire d’Immunopharmacologie, Institut National de la Santé et de la Recherche Médicale Unité 503, Centre d’Etudes et de Recherche en Virologie et Immunologie, Lyon, France;
Laboratoire de Biologie Moléculaire et Cellulaire, Unité Mixte de Recherche 5665 Centre National de la Recherche Scientifique/Ecole Normale Supérieur, Lyon, France; and
Institut National de la Santé et de la Recherche Médicale Unité 404, Centre d’Etudes et de Recherche en Virologie et Immunologie, Institut Fédératif No 128 BioSciences Lyon-Gerland, Lyon, France
High doses of Ag can paradoxically suppress immune responses in vivo. This Ag-specific unresponsiveness (termed high dose tolerance) involves extrathymic mechanisms in mature T lymphocytes. To investigate these mechanisms, we used the in vitro model of PBL activated with anti-CD3 or PHA. In these conditions, increasing mitogen concentrations resulted in a reduction of the proliferative response, associated with an increased percentage of apoptotic cells. Apoptosis did not require prior exposure to IL-2, it was not the consequence of CD178/CD95 or TNF/TNFR interactions, and was therefore clearly distinct from activation-induced cell death. Although the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) decreased DNA fragmentation, cytochrome c release and caspase-9 and caspase-3 activation were not implicated, suggesting that this apoptosis did not primarily involve the intrinsic mitochondrial pathway. E64d, a cysteine protease inhibitor, as well as specific inhibitors of cathepsin B and cathepsin L conferred protection. We further demonstrated that cathepsin B and cathepsin L were released from the lysosomes and catalytically active in the cytosol. Release of cathepsin B and cathepsin L was the consequence of lysosomal membrane permeabilization without complete disruption of the cytosol-lysosome pH gradient. These results demonstrate a role for cathepsins in supraoptimal activation-induced apoptosis in vitro and suggest their possible participation in high dose tolerance in vivo.
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