Antigen-specific elimination of T cells induced by oligomerized hemagglutinin (HA) 306-318.
In a previous study we reported that oligomerized T cell epitopes "superactivated" CD4+ T cells. These oligomers, consisting of 12-16 copies of a peptide epitope derived from the hemagglutinin protein of influenza virus (HA306-318), induced a specific T cell response in amounts as little as 5 pg/ml. We now show that the improved antigenicity of these multimerized epitopes can also be utilized to induce "high zone tolerance". Tolerization, similar to activation, occurred at about 3 logs lower concentration of oligomer than of peptide. HA306-318-specific T cell cultures became nonresponsive to stimulation with peptide after incubation with 0.5-5 microg/ml HA306-318 12-mer. The nonresponsiveness was accompanied by a drastic down-regulation of the TCR and by T cell elimination by apoptotic cell death. In contrast, stimulation with peptide even at 50 microg/ml led to temporary induction of anergy. Consequently, induction of tolerance with the oligomer was permanent and no recovery of the cultures was seen in recall experiments 12-14 days after high zone exposure to the 12-mer.
Falk
K
K
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Rötzschke
O
O
Strominger
J L
JL
D000956:Antigens, Viral / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001704:Biopolymers / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D017635:Clonal Anergy; D004353:Drug Evaluation, Preclinical; D000939:Epitopes / Q000276:immunology / Q000494:pharmacology*; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D016130:Immunophenotyping; D009980:Influenza A virus / Q000276:immunology; D008212:Lymphocyte Depletion / Q000379:methods*; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology
D000956:Antigens, Viral; C416074:Asn-Gly-Gln-Ile-Gly-Asn-Asp-Pro-Asn-Arg-Asp-Ile-Leu; D001704:Biopolymers; D000939:Epitopes; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral; D010446:Peptide Fragments; D010455:Peptides; C086595:influenza hemagglutinin (306-318)