ENDOGENOUS PRESENTATION OF A NASCENT ANTIGENIC EPITOPE TO CD8(+) CTL IS MORE EFFICIENT THAN EXOGENOUS PRESENTATION

Citation
Ys. Hahn et al., ENDOGENOUS PRESENTATION OF A NASCENT ANTIGENIC EPITOPE TO CD8(+) CTL IS MORE EFFICIENT THAN EXOGENOUS PRESENTATION, Immunology and cell biology, 74(5), 1996, pp. 394-400
Citations number
33
Categorie Soggetti
Cell Biology",Immunology
Journal title
ISSN journal
08189641
Volume
74
Issue
5
Year of publication
1996
Pages
394 - 400
Database
ISI
SICI code
0818-9641(1996)74:5<394:EPOANA>2.0.ZU;2-P
Abstract
Cytotoxic T lymphocytes (CTL) recognize short antigenic peptides in as sociation with class I MHC molecules at the cell surface. Newly synthe sized viral polypeptides are processed in the cytoplasm and the fragme nts of antigen are transported into the endoplasmic reticulum (ER) via a peptide transporter where they complex with nascent class I molecul es. The peptide-MHC complex is transported to the cell surface and pre sented to CTL. Sequence analysis of endogenously expressed, MHC-associ ated self or viral antigens indicates Chat the naturally processed pep tides bound to class I MHC molecules are in general 9 +/- 1 residues l ong. Peptides bound to specific class I MHC molecules have in common a llele-specific motifs of conserved residues, The motif for the class I K-d molecules has been shown to be nine or 10 residues with the seque nce X-Tyr-(X)6-I/L or X-Tyr-(X)7-I/L. The Tyr residue at the second po sition and the I/L residue at the ninth position are allele-specific a nchor residues which appear to be required for binding of the peptide to K-d. TO examine the stringency of the requirement for Tpr at the se cond position, we have performed saturation mutagenesis of a minigene encoding the class I K-d-restricted influenza HA210-219 site at the Ty r residue 211. A series of 10 mutants was tested for effects on target -cell sensitization. Most amino acid substitutions for the Tyr residue resulted in a loss of endogenous peptide recognition by HA210-219 rea ctive CTL, consistent with the critical rare of the Tyr at the second position for interaction with K-d molecules. One mutant gene-product e ncoding a His substitution for the Tyr residue was recognized by CTL. However, the corresponding synthetic peptide containing a His substitu tion at the dominant anchor position bound only weakly to K-d, and tar get cells created with the peptide were poorly recognized by CTL. The endogenous His-containing peptide was also less stably associated with class I MHC K-d molecules al the cell surface than the wild-type Tyr peptide, These data indicate that endogenous antigenic peptides may bi nd newly-synthesized class I MHC molecules in the ER more efficiently than fully formed class I molecules at the cell surface and that endog enous peptides may dissociate from class I MHC molecules at different rates. The implications of these findings for CTL recognition and epit ope mapping an discussed.