Crossreactive recognition of viral, self, and bacterial peptide ligands byhuman 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, RAK-FKQLL, located in the Epstein-Barr virus immedi ate-early antigen, BZLF1, is characterized by a diverse T cell receptor (TC R) 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 p rotein. Thus CTL clones that recognized the viral, self, and bacterial pept ides expressed a highly restricted ap TCR phenotype. The CTL clones that re cognized viral and self peptides were more oligoclonal, whereas clones that strictly recognized the viral peptide displayed a diverse TCR profile. Int erestingly, 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 d ilution assays, whereas the cognate peptide,vas highly immunogenic. The des cribed cross-reactions show that human antiviral, CD8(+) Cm responses can b e shaped by peptide ligands derived from autoantigens and environmental bac terial antigens, thereby providing a firm structural basis for molecular mi micry involving class I-restricted CTLs in the pathogenesis of autoimmune d isease.