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A measles virus glycoprotein-derived human CTL epitope is abundantly presented via the proteasomal-dependent MHC class I processing pathway

Laboratory of Vaccine Research¹, Laboratory of Organic Analytical Chemistry², Laboratory of Pathology and Immunobiology³, National Institute of Public Health and the Environment, PO Box 1, 3720 BA Bilthoven, The Netherlands
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands⁴

Author for correspondence: Carla Herberts. Fax +31 30 274 4429. e-mail carla.herberts{at}rivm.nl

Peptides derived from measles virus (MV) are presented by MHC class I molecules at widely divergent levels, but it is currently unknown how functional these levels are. Here, for the first time, we studied the natural occurrence and the underlying processing events of a known MV CTL epitope derived from the fusion glycoprotein (MV-F) and restricted via HLA-B*2705. Using MHC–peptide elution of MV-infected cells followed by sensitive mass spectrometry we determined the naturally occurring sequence to be RRYPDAVYL, corresponding to MV-F_438–446. Its level of expression was enumerated at approximately 1500 copies per cell, which is considered to be abundant, but lies within the range described for other viral CTL epitopes in human MHC class I molecules. We found that processing of the MV-F_438–446 epitope occurs primarily via the classic MHC class I loading pathway, since presentation to CTL depends on both the transporter associated with antigen presentation (TAP) and the proteasome. Even though it is cotranslationally inserted into the ER, a major part of MV-F is located in the cytosol, where it accumulates rapidly in the presence of proteasome inhibitors. We therefore conclude that a substantial cytosolic turnover of MV-F, together with some excellent processing features of MV-F_438–446 precursors, such as precise C-terminal excision by proteasomes, efficient TAP transport and strong HLA binding, dictate the abundant functional expression of the MV-F_438–446 CTL epitope in HLA-B*2705 at the surface of MV-infected cells.

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