Kurzfassung

Proteasomes and aminopeptidases inside the cytosol and the ER are crucially involved in the generation of peptides which are recognized by cytotoxic T-lymphocytes including peptides derived from tumor-associated or –specific proteins. In addition, the contribution of Tripeptidyl peptidase II (TPPII) to the generation of CTL epitopes has recently by reported for an HLA-A3 restricted CTL epitope derived from the HIV Nef protein. Therefore, we attempt to extend the current knowledge on the...Proteasomes and aminopeptidases inside the cytosol and the ER are crucially involved in the generation of peptides which are recognized by cytotoxic T-lymphocytes including peptides derived from tumor-associated or –specific proteins. In addition, the contribution of Tripeptidyl peptidase II (TPPII) to the generation of CTL epitopes has recently by reported for an HLA-A3 restricted CTL epitope derived from the HIV Nef protein. Therefore, we attempt to extend the current knowledge on the specificity of these proteases and their effect on the generation of tumor-specific CTL epitopes. The final goal is to predict the contribution of these proteases and their specificities in order to allow, in combination with predictions of MHC-peptide interactions, a rapid and reliable identification of CTL epitopes in any given tumorspecific or-associated protein.
For this purpose we will analyse the proteolytic specificities of aminopeptidases involved in trimming of CTL ligand precursors. This includes the cytosolic proteases TPPII, Bleomycin hydrolase (BH) and Puromycin sensitive aminopeptidase (PSA) recently identified by us as being involved in the generation of CTL epitopes. All enzymes can be analyzed in vitro using purified or recombinant proteins and in vivo in knock-out mice (for PSA and BH). The implementation of cleavage specificity of these proteases in the prediction of CTL epitopes might help to identify especially those CTL epitopes where the proteasome is only responsible for the generation of C- but not the N-terminus.
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