Crossreactive recognition of viral, self, and bacterial peptide ligands by human class I-restricted cytotoxic T lymphocyte clonotypes: implications for molecular mimicry in autoimmune disease.
The immunodominant, CD8(+) cytotoxic T lymphocyte (CTL) response to the HLA-B8-restricted peptide, RAKFKQLL, located in the Epstein-Barr virus immediate-early antigen, BZLF1, is characterized by a diverse T cell receptor (TCR) repertoire. Here, we show that this diversity can be partitioned on the basis of crossreactive cytotoxicity patterns involving the recognition of a self peptide-RSKFRQIV-located in a serine/threonine kinase and a bacterial peptide-RRKYKQII-located in Staphylococcus aureus replication initiation protein. Thus CTL clones that recognized the viral, self, and bacterial peptides expressed a highly restricted alphabeta TCR phenotype. The CTL clones that recognized viral and self peptides were more oligoclonal, whereas clones that strictly recognized the viral peptide displayed a diverse TCR profile. Interestingly, the self and bacterial peptides equally were substantially less effective than the cognate viral peptide in sensitizing target cell lysis, and also resulted only in a weak reactivation of memory CTLs in limiting dilution assays, whereas the cognate peptide was highly immunogenic. The described crossreactions show that human antiviral, CD8(+) CTL responses can be shaped by peptide ligands derived from autoantigens and environmental bacterial antigens, thereby providing a firm structural basis for molecular mimicry involving class I-restricted CTLs in the pathogenesis of autoimmune disease.
Misko
I S
IS
Epstein-Barr Virus Unit, Queensland Institute of Medical Research and Joint Experimental Oncology, University of Queensland, Brisbane, 4029, Australia. ihorM@qimr.edu.au
Cross
S M
SM
Khanna
R
R
Elliott
S L
SL
Schmidt
C
C
Pye
S J
SJ
Silins
S L
SL
D000595:Amino Acid Sequence; D001327:Autoimmune Diseases / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology; D001483:Base Sequence; D003602:Cytotoxicity, Immunologic; D004265:DNA Helicases / Q000276:immunology; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000276:immunology; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D015795:HLA-B8 Antigen / Q000276:immunology*; D004854:Herpesvirus 4, Human / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D013211:Staphylococcus aureus / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000145:classification / Q000276:immunology*; D015534:Trans-Activators / Q000737:chemistry / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology
C063676:BZLF1 protein, Herpesvirus 4, Human; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D015795:HLA-B8 Antigen; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015534:Trans-Activators; D014764:Viral Proteins; C045264:replication initiator protein; D004265:DNA Helicases