Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.
The importance of pairwise interactions between peptide residues in the delineation of TCR specificity.
J Immunol. 1998 Nov 1;161(9):4728-35. Unique Identifier : AIDSLINE MED/99008534 Leggatt GR; Hosmalin A; Pendleton CD; Kumar A; Hoffman S; Berzofsky JA; Molecular Immunogenetics and Vaccine Research Section, Metabolism; Branch, National Cancer Institute, National Institutes of Health,; Bethesda, MD 20892-1578, USA.
Abstract:
A minimal, nonamer epitope (TEMEKEGKI) from the reverse transcriptase protein of HIV-1, restricted by H-2Kk, was identified and the function of individual residues determined. Besides classical anchor residues at positions 2 and 9, methionine at position 3 was identified as an important MHC anchor and improved binding of a different (malarial) nonamer epitope to H-2Kk, albeit while also abolishing CTL recognition. Lysine at position 5 was replaceable by alanine for CTL raised against wild-type peptide but abolished recognition for CTL raised against the variant 5ALA peptide, indicating a unidirectional cross-reactivity. Interestingly, one CTL line raised against the 5ALA substituted peptide was permissive for a double substitution at positions 5 and 6, in which lysine was permissive at position 5 only if the adjacent glutamic acid was replaced by alanine. Extensive analysis revealed three distinct patterns of responses with peptides doubly substituted in this region: recognition of both single substitutions but not the double substitution, recognition of only one single substitution but also the double substitution, or recognition of both single substitutions and the double substitution. A second complementary substitution can therefore restore function lost through a first substitution. Thus, no residue acts independently of its neighbors, and pairs of substitutions may give results not predictable from the effects of each taken singly. This finding may have bearing on viral infections (such as HIV), in which the accumulation of two mutations in the epitope may lead to the reengagement of memory CTL previously silenced by the initial mutation.
Keywords: JOURNAL ARTICLE Amino Acid Substitution Animal Chemistry, Physical Comparative Study Cross Reactions Epitopes/CHEMISTRY/GENETICS/IMMUNOLOGY H-2 Antigens/*IMMUNOLOGY HIV-1/IMMUNOLOGY HIV-1 Reverse Transcriptase/CHEMISTRY/GENETICS/*IMMUNOLOGY L Cells (Cell Line) Mice Mice, Inbred C3H Oligopeptides/CHEMISTRY/CHEMICAL SYNTHESIS/IMMUNOLOGY Plasmodium falciparum/IMMUNOLOGY Protein Binding Protein Conformation Protozoan Proteins/CHEMISTRY/*IMMUNOLOGY Receptors, Antigen, T-Cell/*CHEMISTRY/IMMUNOLOGY/METABOLISM T-Lymphocytes, Cytotoxic/*IMMUNOLOGY 990130
A9910558
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Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.
