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PMID: 7523572 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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 Journal of experimental medicine ·Vol. 180 ·No. 4 ·1994-10-01 ·Pages 1471-83

Chen W, Khilko S, Fecondo J, Margulies DH, McCluskey J

Abstract

The contribution of major histocompatibility complex (MHC) class I-peptide 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-2Kb-restricted binding and presentation of the immunodominant ovalbumin (OVA)257-264 (SIINFEKL) determinant to that of a subdominant OVA determinant OVA55-62 (KVVRFDKL). Immunodominance of OVA257-264 was not attributable to the specific T cell repertoire but correlated instead with more efficient Ag presentation. This enhanced Ag presentation could be accounted for by the higher affinity of Kb/OVA257-264 compared with Kb/OVA55-62 despite the presence of a conserved Kb-binding motif in both peptides. Kinetic binding studies using purified soluble H-2Kb molecules (Kbs) and biosensor techniques indicated that the Kon for association of OVA257-264-C6 and Kbs at 25 degrees C was integral of 10-fold faster (5.9 x 10(3) M-1 s-1 versus 6.5 x 10(2) M-1 s-1), and the Koff 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 OVA55-62-C6 and Kbs. The association of these peptides with Kb was significantly influenced by multiple residues at presumed nonanchor sites within the peptide sequence. The contribution of each peptide residue to Kb-binding was dependent upon the sequence context and the summed contributions were not additive. Thus the affinity of MHC class I-peptide binding is a critical factor controlling presentation of peptide Ag and immunodominance in the class I-restricted CTL response.

MeSH Terms
Amino Acid Sequence Epitopes H-2 Antigens/metabolism Humans Molecular Sequence Data Ovalbumin/immunology,metabolism Peptide Fragments/immunology,metabolism T-Lymphocytes, Cytotoxic/immunology Tumor Cells, Cultured
Chemicals
Epitopes H-2 Antigens H-2Kb protein, mouse Peptide Fragments Ovalbumin
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Chen W
Centre for Transfusion Medicine & Immunology, Flinders Medical Centre, Bedford Park, Australia.
Khilko S
Fecondo J
Margulies D H
McCluskey J
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.180.4.1471
Published
1994-10-01
Pages
1471-83
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2191679
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.180.4.1471 PMC Full Text View journal details
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