title: Avoidance of self-reactivity results in skewed CTL responses to rare components of synthetic immunogens.
abstract: In studying the CTL recognition of peptide determinants derived from the nuclear Ag La (SS-B), we observed significant skewing of the response toward rare components present within the immunogen. Thus, priming of naive mouse lymphocytes in vitro with a synthetic H-2Kb-binding peptide comprising human La (hLa) residues 51-58 resulted in class I-restricted cytotoxic T cells that failed to recognize naturally presented hLa 51-58 peptide. Instead, the majority of T hybrids recognized a low abundance (< or = 1%) contaminant present at picomolar concentrations in the original synthesis and identified as a peptide adduct containing N,4-t-butyl asparagine at position 6 of the hLa 51-58 sequence. The preferred T cell recognition of the butyl adduct was not due to increased affinity of this peptide for the H-2Kb molecule or to the antagonism of CTL recognizing the unmodified determinant. Rather, the bias in the immune response appeared to be the result of partial self-tolerance to the homologous mouse La 51-58 determinant, which differs from its human counterpart by only a single amino acid at position 1 (T-->I). Accordingly, the CTL response appeared to be focused on "non-self" ligands present within the synthesis, even though they were present at very low concentrations. These observations have significant implications for the use of synthetic peptide vaccines, especially those designed to manipulate responses to self peptides such as tumor Ags in which self-tolerance may result in unexpected reactivity.
authors.affiliation: The Department of Clinical Immunology, Centre for Transfusion Medicine and Immunology, Flinders Medical Center, Bedford Park, South Australia. A.Purcell@microbiology.unimelb.edu.au
authors.forename: A W
authors.initials: AW
authors.lastname: Purcell
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.forename: N J
authors.initials: NJ
authors.lastname: Ede
authors.forename: J J
authors.initials: JJ
authors.lastname: Gorman
authors.forename: J V
authors.initials: JV
authors.lastname: Fecondo
authors.forename: D C
authors.initials: DC
authors.lastname: Jackson
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.forename: J
authors.initials: J
authors.lastname: McCluskey
mesh_terms: D019943:Amino Acid Substitution / Q000276:immunology; D000818:Animals; D001216:Asparagine / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology* / Q000302:isolation & purification / Q000378:metabolism; D005591:Chemical Fractionation; D002851:Chromatography, High Pressure Liquid; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006183:H-2 Antigens / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D007739:L Cells; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology* / Q000302:isolation & purification / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D012261:Ribonucleoproteins / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013945:Thymoma; D014407:Tumor Cells, Cultured; D000097585:SS-B Antigen
chemical_list: D001216:Asparagine; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D012261:Ribonucleoproteins; D000097585:SS-B Antigen