title: Cytotoxic T cell repertoire selection. A single amino acid determines alternative class I restriction.
abstract: CTL responses are governed by intracellular Ag processing, affinity of peptides for MHC class I molecules, and the T cell repertoire. In this report we demonstrate that a class I Dd-restricted 10-mer CTL epitope within the gp160 envelope glycoprotein of HIV-1 strain IIIB (residues 318-327) contains a 9-amino acid peptide (residues 319-327), which efficiently binds to both the Dd and Ld class I molecules in vitro. The potential for broadening the naturally limited CTL response to include presentation on the Ld class I molecules in vivo was examined using a minigene-based vaccine strategy to insure cytosolic expression of "preprocessed" forms of the gp160 epitope. Immunization with recombinant vaccinia viruses (vac) expressing either the gp160 10 mer or 9 mer, both including an initiation methionine (M318-327 and M319-327, respectively), induced predominantly Dd-restricted CTL specific for native gp160. By contrast, recombinant vac expressing eight gp160 amino acids (M320-327) generated predominantly Ld-restricted CTL which are specific for synthetic gp160 peptides but not native gp160. The ability to induce Ld-restricted CTL suggests that the absence of an Ld-restricted response to native gp160 cannot be attributed to a limited T cell repertoire, but to inefficient processing of gp160 for presentation on Ld. The switch in class I restriction, controlled by a single amino acid within one epitope, demonstrates that nonanchor residues have a profound effect on differential MHC restriction and CTL induction. Thus, minigene-based vaccines expressing minimal epitopes may be useful in inducing a more heterogeneous CTL response than previously appreciated.
authors.affiliation: Department of Neurology, University of Southern California School of Medicine, Los Angeles 90033.
authors.forename: C C
authors.initials: CC
authors.lastname: Bergmann
authors.forename: L
authors.initials: L
authors.lastname: Tong
authors.forename: R V
authors.initials: RV
authors.lastname: Cua
authors.forename: J L
authors.initials: JL
authors.lastname: Sensintaffar
authors.forename: S A
authors.initials: SA
authors.lastname: Stohlman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D001483:Base Sequence; D001667:Binding, Competitive; D003602:Cytotoxicity, Immunologic; D004274:DNA, Recombinant / Q000235:genetics; D000939:Epitopes / Q000378:metabolism; D015686:Gene Products, env / Q000235:genetics* / Q000276:immunology*; D019302:HIV Envelope Protein gp160; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D007114:Immunization; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000235:genetics / Q000276:immunology; D011498:Protein Precursors / Q000235:genetics* / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D004274:DNA, Recombinant; D000939:Epitopes; D015686:Gene Products, env; D019302:HIV Envelope Protein gp160; D015395:Histocompatibility Antigens Class I; D009842:Oligopeptides; D011498:Protein Precursors