PEPTIDE VACCINATION WITH AN ANCHOR-REPLACED CTL EPITOPE PROTECTS AGAINST HUMAN-PAPILLOMAVIRUS TYPE 16-INDUCED TUMORS EXPRESSING THE WILD-TYPE EPITOPE

Citation
Mpm. Vierboom et al., PEPTIDE VACCINATION WITH AN ANCHOR-REPLACED CTL EPITOPE PROTECTS AGAINST HUMAN-PAPILLOMAVIRUS TYPE 16-INDUCED TUMORS EXPRESSING THE WILD-TYPE EPITOPE, Journal of immunotherapy, 21(6), 1998, pp. 399-408
Citations number
50
Categorie Soggetti
Immunology,"Medicine, Research & Experimental",Oncology
Journal title
ISSN journal
15249557
Volume
21
Issue
6
Year of publication
1998
Pages
399 - 408
Database
ISI
SICI code
1524-9557(1998)21:6<399:PVWAAC>2.0.ZU;2-0
Abstract
Anchor residues in cytotoxic T-lymphocyte (CTL) epitope-bearing peptid es are buried deep in the major histocompatibility complex (MHC) class I antigen-presenting groove and are essential for binding to MHC clas s I molecules. We investigated whether anchor residue replacement affe cts the ability of a CTL epitope to be bound and transported by MHC cl ass I molecules and transporter associated with antigen (TAP), respect ively, and affects its functionality in vivo. Therefore, both anchor r esidues, at positions 5 and 9, of the H-2D(b)-restricted CTL epitope H PV16 E7 49-57 RAHYNIVTF were systematically exchanged for one of the 1 9 other naturally occurring amino acid (AA). Only replacement at ancho r position 9 with residues V, I, L, or M, which are documented D-b mot if-anchor residues at that position, allowed binding to the MHC class I H-2D(b) molecule as well as transport by TAP with the same efficienc y as the wild-type epitope. In B6 mice (H-2(b)), these anchor-modified peptide epitopes efficiently induced CTL that specifically recognized the wild-type epitope. Conversely, wild-type epitope-induced CTL reco gnized the V9-, I9-, L9-, and M9-replaced epitopes, respectively. In t erms of tumor protection against a challenge with HPV16-transformed ce lls, the VB-replaced epitope was as efficient as the wild-type epitope E7 49-57. Taken together, our data demonstrate that specific CTL epit ope anchor replacements are allowed with respect to MHC class I bindin g and TAP transport, as well as with respect to antigenicity and immun ogenicity in vivo. The results presented are relevant to CTL epitope-b ased peptide vaccine development.