title: Inactivation of human immunodeficiency virus (HIV)-1 envelope-specific CD8+ cytotoxic T lymphocytes by free antigenic peptide: a self-veto mechanism?
abstract: Free peptide has been found to inhibit cytotoxic T lymphocyte (CTL) activity, and veto cells bearing peptide-major histocompatibility complex (MHC) complexes have been found to inactivate CTL, but the two phenomena have not been connected. Here we show that a common mechanism may apply to both. CD8+ CTL lines or clones specific for a determinant of the human immunodeficiency virus (HIV) 1 IIIB envelope protein gp160, P18IIIB, are inhibited by as little as 10 min exposure to the minimal 10-mer peptide, I-10, within P18IIIB, free in solution, in contrast to peptide already bound to antigen-presenting cells (APC), which does not inhibit. Several lines of evidence suggest that the peptide must be processed and presented by H-2Dd on the CTL itself to the specific T cell receptor (TCR) to be inhibitory. The inhibition was not killing, in that CTL did not kill 51Cr-labeled sister CTL in the presence of free peptide, and in mixing experiments with CTL lines of different specificities restricted by the same MHC molecule, Dd, the presence of free peptide recognized by one CTL line did not inhibit the activity of the other CTL line that could present the peptide. Also, partial recovery of activity could be elicited by restimulation with cell-bound peptide, supporting the conclusion that neither fratricide nor suicide (apoptosis) was involved. The classic veto phenomenon was ruled out by failure of peptide-bearing CTL to inactivate others. Using pairs of CTL lines of differing specificity but similar MHC restriction, each pulsed with the peptide for which the other is specific, we showed that the minimal requirement is simultaneous engagement of the TCR and class I MHC molecules of the same cell. This could occur in single cells or pairs of cells presenting peptide to each other. Thus, mechanistically, the inhibition is analogous to veto, and might be called self-veto. As a clue to a possible mechanism, we found that free I-10 peptide induced apparent downregulation of expression of specific TCR as well as interleukin 2 receptor, CD69, lymphocyte function-associated antigen 1, and CD8. This self-veto effect also has implications for in vivo immunization and mechanisms of viral escape from CTL immunity.
authors.affiliation: Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Takahashi
authors.forename: Y
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: G R
authors.initials: GR
authors.lastname: Leggatt
authors.forename: Y
authors.initials: Y
authors.lastname: Ishida
authors.forename: T
authors.initials: T
authors.lastname: Saito
authors.forename: K
authors.initials: K
authors.lastname: Yokomuro
authors.forename: J A
authors.initials: JA
authors.lastname: Berzofsky
mesh_terms: D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D002999:Clone Cells; D000939:Epitopes / Q000494:pharmacology; D015686:Gene Products, env / Q000494:pharmacology*; D019302:HIV Envelope Protein gp160; D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D018448:Models, Immunological; D008969:Molecular Sequence Data; D011498:Protein Precursors / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology* / Q000821:virology
chemical_list: D000939:Epitopes; D015686:Gene Products, env; D019302:HIV Envelope Protein gp160; D011498:Protein Precursors