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Volume 271, Number 30, Issue of July 26, 1996 pp. 17829-17836
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Binding of Viral Antigens to Major Histocompatibility Complex Class I H-2D^b Molecules Is Controlled by Dominant Negative Elements at Peptide Non-anchor Residues
IMPLICATIONS FOR PEPTIDE SELECTION AND PRESENTATION

(Received for publication, February 23, 1996, and in revised form, April 4, 1996)

Denis Hudrisier , Honoré Mazarguil , Françoise Laval , Michael B. A. Oldstone ^§ and Jean Edouard Gairin

From the  Institut de Pharmacologie et de Biologie Structurale, CNRS, 205 route de Narbonne, 31400 Toulouse, France and ^§ The Scripps Research Institute, Department of Neuropharmacology, Division of Virology, La Jolla, California 92037

Binding of viral antigens to major histocompatibility complex (MHC) class I molecules is a critical step in the activation process of CD8⁺ cytotoxic T lymphocytes. In this study, we investigated the impact of structural factors at non-anchor residues in peptide-MHC interaction using the model of lymphocytic choriomeningitis virus (LCMV) infection of its natural host, the mouse. Altering viral genes by making reassortants, recombinants, and using synthetic peptides, CD8⁺ cytotoxic T lymphocytes were shown to recognize only three H-2D^b-restricted epitopes, GP amino acids 33-41/43, GP 276-286, and NP 396-404. However, LCMV NP and GP proteins contain 31 other peptides bearing the H-2D^b motif. These 34 LCMV peptides and 11 other known H2-D^b-restricted peptides were synthesized and examined for MHC binding properties. Despite the presence of the H-2D^b binding motif, the majority of LCMV peptides showed weak or no affinity for H-2D^b. We observed that dominant negative structural elements located at non-anchor positions played a crucial role in peptide-MHC interaction. By comparative sequence analysis of strong versus non-binders and using molecular modeling, we delineated these negative elements and evaluated their impact on peptide-MHC interaction. Our findings were validated by showing that a single mutation of a favorable non-anchor residue in the sequence of known viral epitopes for a negative element resulted in dramatic reduction of antigen presentation properties, while conversely, substitution of one negative for a positive element in the sequence of a non-binder conferred to the peptide an ability to now bind to MHC molecules.

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