CTL recognition of an altered peptide associated with asparagine bond rearrangement. Implications for immunity and vaccine design.
The extent to which peptides containing chemically and post-translationally modified amino acid side chains are recognized by primed CTL has not been clearly defined. We report on the CTL recognition of a MHC class I-restricted peptide containing a cyclized asparagine (succinimide) residue. This modification of the asparagine side chain is a common intermediate structure during deamidation, isomerization, and bond rearrangements of amide-containing amino acids and also occurs as a side reaction in peptide synthesis. The CTL specifically recognized the succinimide-containing peptide showing only weak cross-reactivity at high concentrations of the parent peptide containing unmodified asparagine. Similarly, CTL raised against the parent peptide did not recognize the succinimide derivative of this peptide. Naturally processed forms of these structures are likely to occur given the importance and frequency of deamidation both in vitro and in vivo. Moreover, since succinimide intermediates of deamidated peptides can occasionally be very stable, these peptides have the potential to act as altered self-Ags with significant implications for autoimmunity. In addition, unwanted and potentially hazardous specificities may be elicited when using synthetic peptides in subunit vaccines in which succinimide residues may form spontaneously during storage or chemical synthesis.
Chen
W
W
Department of Clinical Immunology, Flinders Medical Centre, South Australia, Australia.
Ede
N J
NJ
Jackson
D C
DC
McCluskey
J
J
Purcell
A W
AW
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D001216:Asparagine / Q000737:chemistry / Q000276:immunology*; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology*; D002851:Chromatography, High Pressure Liquid; D006183:H-2 Antigens / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D012261:Ribonucleoproteins / Q000737:chemistry / Q000276:immunology*; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000737:chemistry / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology; D014407:Tumor Cells, Cultured; D000097585:SS-B Antigen
D001216:Asparagine; D001324:Autoantigens; D006183:H-2 Antigens; D015395:Histocompatibility Antigens Class I; D012261:Ribonucleoproteins; D013388:Succinimides; D014157:Transcription Factors; D000097585:SS-B Antigen; C032876:H-2Kb protein, mouse; C032620:succinimide