Peptide vaccination with an anchor-replaced CTL epitope protects against human papillomavirus type 16-induced tumors expressing the wild-type epitope.
Anchor residues in cytotoxic T-lymphocyte (CTL) epitope-bearing peptides are buried deep in the major histocompatibility complex (MHC) class I antigen-presenting groove and are essential for binding to MHC class I molecules. We investigated whether anchor residue replacement affects the ability of a CTL epitope to be bound and transported by MHC class I molecules and transporter associated with antigen (TAP), respectively, and affects its functionality in vivo. Therefore, both anchor residues, at positions 5 and 9, of the H-2Db-restricted CTL epitope HPV16 E7 49-57 RAHYNIVTF were systematically exchanged for one of the 19 other naturally occurring amino acid (AA). Only replacement at anchor position 9 with residues V, I, L, or M, which are documented Db motif-anchor residues at that position, allowed binding to the MHC class I H-2Db molecule as well as transport by TAP with the same efficiency as the wild-type epitope. In B6 mice (H-2b), these anchor-modified peptide epitopes efficiently induced CTL that specifically recognized the wild-type epitope. Conversely, wild-type epitope-induced CTL recognized the V9-, I9-, L9-, and M9-replaced epitopes, respectively. In terms of tumor protection against a challenge with HPV16-transformed cells, the V9-replaced epitope was as efficient as the wild-type epitope E7 49-57. Taken together, our data demonstrate that specific CTL epitope anchor replacements are allowed with respect to MHC class I binding and TAP transport, as well as with respect to antigenicity and immunogenicity in vivo. The results presented are relevant to CTL epitope-based peptide vaccine development.
Vierboom
M P
MP
Department of Immunohematology & Blood Bank, University Hospital Leiden, The Netherlands.
Feltkamp
M C
MC
Neisig
A
A
Drijfhout
J W
JW
ter Schegget
J
J
Neefjes
J J
JJ
Melief
C J
CJ
Kast
W M
WM
D000595:Amino Acid Sequence; D000818:Animals; D000937:Antigen-Antibody Reactions; D002460:Cell Line; D002472:Cell Transformation, Viral; D003429:Cross Reactions; D000939:Epitopes; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D051379:Mice; D027383:Papillomaviridae / Q000276:immunology*; D030361:Papillomavirus Infections / Q000276:immunology*; D010455:Peptides / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014412:Tumor Virus Infections / Q000276:immunology*; D014611:Vaccination
D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D010455:Peptides