DETERMINANT SELECTION OF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS I-RESTRICTED ANTIGENIC PEPTIDES IS EXPLAINED BY CLASS I-PEPTIDE AFFINITY AND IS STRONGLY INFLUENCED BY NONDOMINANT ANCHOR RESIDUES

The contribution of major histocompatibility complex (MHC) class I-pep tide affinity to immunodominance of particular peptide antigens (Ags) in the class I-restricted cytotoxic T lymphocyte (CTL) response is not clearly established. Therefore, we have compared the H-2K(b)-restrict ed binding and presentation of the immunodominant ovalbumin (OVA)(257- 264) (SIINFEKL) determinant to that of a subdominant OVA determinant O VA(55-62) (KVVRFDKL). Immuno-dominance of OVA(257-264) was not attribu table to the specific T cell repertoire but correlated instead with mo re efficient Ag presentation. This enhanced Ag presentation could be a ccounted for by the higher affinity of K-b/OVA(257-264) compared with K-b/OVA(55-62) despite the presence of a conserved K-b-binding motif i n both peptides. Kinetic binding studies using purified soluble H-2K(b ) molecules (K-s(b)) and biosensor techniques indicated that the K-on for association of OVA(257-264-C6) and K-s(b) at 25 degrees C was simi lar to 10-fold faster (5.9 x 10(3) M(-1) s(-1) versus 6.5 x 10(2) M(-1 ) s(-1)), and the K-off approximately twofold slower (9.1 x 10(-6) s(- 1) versus 1.6 x 10(-5) s(-1)), than the rate constants for interaction of OVA(55-62-C6) and K-s(b). The association of these peptides with K -b was significantly influenced by multiple residues at presumed nonan chor sites within the peptide sequence. The contribution of each pepti de residue to K-b-binding was dependent upon the sequence context and the summed contributions were not additive. Thus the affinity of MHC c lass I-peptide binding is a critical factor controlling presentation o f peptide Ag and immunodominance in the class I-restricted CTL respons e.