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Infection and Immunity, June 2002, p. 3249-3258, Vol. 70, No. 6
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.6.3249-3258.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Enhanced Delivery of Exogenous Peptides into the Class I Antigen Processing and Presentation Pathway

Lolke de Haan,1 Arron R. Hearn,2 A. Jennifer Rivett,2 and Timothy R. Hirst1*

Departments of Pathology & Microbiology,1 Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom2

Received 17 December 2001/ Returned for modification 1 February 2002/ Accepted 7 March 2002

Current immunization strategies, using peptide or protein antigens, generally fail to elicit cytotoxic-T-lymphocyte responses, since these antigens are unable to access intracellular compartments where loading of major histocompatibility complex class I (MHC-I) molecules occurs. In an attempt to circumvent this, we investigated whether the GM1 receptor-binding B subunit of Escherichia coli heat-labile toxin (EtxB) could be used to deliver class I epitopes. When a class I epitope was conjugated to EtxB, it was delivered into the MHC-I presentation pathway in a GM1-binding-dependent fashion and resulted in the appearance of MHC-I-epitope complexes at the cell surface. Importantly, we show that the efficiency of EtxB-mediated epitope delivery could be strikingly enhanced by incorporating, adjacent to the class I epitope, a 10-amino-acid segment from the C terminus of the DNA polymerase (Pol) of herpes simplex virus. The replacement of this 10-amino-acid segment by a heterologous sequence or the introduction of specific amino acid substitutions within this segment either abolished or markedly reduced the efficiency of class I epitope delivery. If the epitope was extended at its C terminus, EtxB-mediated delivery into the class I presentation pathway was found to be completely dependent on proteasome activity. Thus, by combining the GM1-targeting function of EtxB with the 10-amino-acid Pol segment, highly efficient delivery of exogenous epitopes into the endogenous pathway of class I antigen processing and presentation can be achieved.

* Corresponding author. Mailing address: Department of Pathology & Microbiology, University of Bristol, School of Medical Sciences, University Walk, Bristol BS8 1TD, United Kingdom. Phone: 44-117-9287538. Fax: 44-117-9300543. E-mail: t.r.hirst{at}bristol.ac.uk.

Editor: J. T. Barbieri

Infection and Immunity, June 2002, p. 3249-3258, Vol. 70, No. 6
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.6.3249-3258.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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