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Sequence tags enhancing intracellular epitope transport and presentation

Our strategy aims at enhancing the step of intracellular peptide transport into the endoplasmic reticulum by the TAP transporters to increase presentation of peptides to cytotoxic T cells. While the selectivity of the TAP pumps has been known for some time, a possible benefit of modulating TAP affinity for enhancing peptide presentation has so far neither been proposed nor tested. We have analyzed the effect of defined aminoterminal extensions on the efficiency of TAP transport and of presentation to T cells of several epitopes.

In these studies, we have defined several sequences of between 1 and 3 residues that, upon addition to the aminoterminus of a peptide, increase TAP transporter affinity dramatically for all tested peptides. Moreover, for several epitopes, we have demonstrated that such extensions lead to highly efficient and increased epitope presentation to T lymphocytes. For peptide epitoeps with low TAP affinities, standard 3-amino acid extensions can be used that universalle enhcance TAP affinity. For peptides with intermediate TAP afffinity, individually designed extenions by one or two residues are preferrable.

The mentioned extensions can be added to single epitopes but also used as linkers between two epitopes in synthetic poly-epitopes. Sequences designed to link poly-epitopes are also designed to minimize cleavage by cytosolic proteases (proteasome) within or after the linker but to increase cleavage before the linker. Such linkers are therefore designed to ensure optimal release from poly-epitopes of individual peptides in a form providing efficient access to the ER.

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