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Abstract
Reference
The role of the proteasome in generating cytotoxic T cell epitopes:
Insights obtained from improved predictions of proteasomal cleavage
M. Nielsen, C. Lundegaard, S. Brunak, O. Lund, and C. Kesmir. Manuscript
accepted for publication in European Journal of Immunology May 2005.
Abstract
Reverse immunogenetic approaches attempt to optimize the selection of
candidate epitopes and thus minimize the experimental effort needed to
identify new epitopes. When predicting CTL epitopes, the main focus has
been on the highly specific MHC class I binding event. Methods have
also been developed for predicting the antigen processing steps
preceding MHC class I binding including proteasomal cleavage and
transporter associated with antigen processing (TAP) transport
efficiency. Here, we use a dataset obtained from the SYFPEITHI database
to show that a method integrating predictions of MHC class I binding
affinity, TAP transport efficiency, and C-terminal proteasomal cleavage
outperforms any of the individual methods. Using an independent
evaluation dataset of HIV epitopes from the Los Alamos database, the
validity of the integrated method is confirmed. The performance of the
integrated method is found to be significantly higher than that of the
two publicly available prediction methods BIMAS and SYFPEITHI. In order
to identify 85% of the epitopes in the HIV dataset, 9% and 10% of all
possible 9mers in the HIV proteins must be tested if using the BIMAS
and SYFPEITHI methods, respectively, for the selection of candidate
epitopes. This number is reduced to 7% when using the integrated
method. In practical terms, this means that the experimental effort
needed in order to identify an epitope in a hypothetical protein with
85% probability is reduced by 20-30% when using the integrated method.
The method is available at http://www.cbs.dtu.dk/services/NetCTL.
Supplementary material is available at http://www.cbs.dtu.dk/suppl/immunology/CTL.php.
CORRESPONDENCE
Morten Nielsen,
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