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Molecular Analysis of TCR and Peptide/MHC Interaction Using P18-I10-Derived Peptides with a Single D-Amino Acid Substitution

Yohko Nakagawa ^*, Hiroto Kikuchi  and Hidemi Takahashi ^*

^* Department of Microbiology and Immunology and Department of Physics, Nippon Medical School, Tokyo 113-8602, Japan

Correspondence: Address reprint requests to Hidemi Takahashi, Department of Microbiology and Immunology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan. Tel.: 81-3-3822-2131 ext. 5381; Fax: 81-3-3316-1904; E-mail: htkuhkai{at}nms.ac.jp.

For the structural analysis of T-cell receptor (TCR) and peptide/MHC interaction, a series of peptides with a single amino acid substitution by a corresponding D-amino acid, having the same weight, size, and charge, within P18-I10 (aa318–327: RGPGRAFVTI), an immunodominant epitope of HIV-1 IIIB envelope glycoprotein, restricted by the H-2D^d class I MHC molecule, has been synthesized. Using those peptides, we have observed that the replacement at positions 324F, 325V, 326T, and 327I with each corresponding D-amino acid induced marked reduction of the potency to sensitize targets for P18-I10-specific murine CD8⁺ cytotoxic T lymphocytes (CTLs), LINE-IIIB, recognition. To analyze further the role of amino acid at position 325, the most critical site for determining epitope specificity, we have developed a CTL line [LINE-IIIB(325D)] and its offspring clones specific for the epitope I-10(325v) having a D-valine (v) at position 325. Taking advantage of two distinct sets of CD8⁺ CTLs restricted by the same D^d, three-dimensional structural analysis on TCR and peptide/MHC complexes by molecular modeling was performed, which indicates that the critical amino acids within the TCRs for interacting with 325V or 325v appear to belong to the complementarity-determining region 1 but not to the complementarity-determining region 3 of Vβ chain.