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Granzyme B-mediated Degradation of T-Cell Receptor Chain¹

Departments of Pathology [E. W., G-Q. W., L. A. G., H. R.], and Otolaryngology [B. R. G.], The University of Pittsburgh School of Medicine, and The University of Pittsburgh Cancer Institute [H. R.], Pittsburgh, Pennsylvania 15213

We recently reported that the T-cell receptor (TCR)- chain is cleaved bycaspase-3 and -7 in apoptotic T lymphocytes or in a cell-free system. Wereport here that the chain is also a direct substrate for granzyme B (GrB) proteolytic activity. Loss in expression of TCR- was observed in Jurkat T leukemic cells treated by a combination of GrB and a replication-deficient adenovirus. Although the apoptosis initiated in these cells by GrB was significantly reduced by the pancaspase inhibitor Z-VAD-FMK, TCR- degradation was not prevented. These findings suggest that the GrB-mediated degradation of TCR- chain can proceed despite the efficient inhibition of caspase activity. An in vitro translated TCR- product was efficiently cleaved by GrB, which suggests that the TCR- protein is a direct substrate for GrB. As assessed by site-directed mutagenesis, the activity of GrB was directed toward aspartic acid residues that were different from those of recombinant caspase-3. Whereas caspase-3 cleavage products appear to accumulate, the GrB-generated products seem to undergo further degradation, which suggests the presence of multiple GrB-specific cleavage sites within the TCR- protein. These findings suggest that the TCR- protein in target T lymphocytes serves as a substrate for the proteolytic activities that are featured by the two major mechanisms of cytotoxicity: death receptor pathways mediated by caspases and granule exocytosis mediated by direct GrB activity or GrB-activated caspases. TCR- protein degradation may be of significance in cytotoxic mechanisms directed against T cells infected with viruses, such as HIV-1, in which the TCR- protein is used for viral pathogenesis.

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