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

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

Epstein–Barr Virus Unit, Queensland Institute of Medical Research and Joint Experimental Oncology, University of Queensland, Brisbane, 4029, Australia

Edited by Jack Leonard Strominger, Harvard University, Cambridge, MA, and approved November 24, 1998 (received for review October 26, 1998)

Abstract

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 αβ 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.

Footnotes

↵ † To whom reprint requests should be addressed. e-mail: ihorM{at}qimr.edu.au.
This paper was submitted directly (Track II) to the Proceedings Office.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. AJ235202–AJ235225).
ABBREVIATIONS:

EBV,

Epstein–Barr virus;

CTL,

cytotoxic T lymphocyte;

LCL,

lymphoblastoid cell line;

TCR,

T cell receptor;

BZLF1,

EBV immediate-early antigen;

PBMC,

peripheral blood mononuclear cell;

RAK,

RAKFQLL (residues 190–197);

RSK,

RSKFRQIV (residues 156–163);

RRK,

RRKYKQII (residues 269–276);

V-(D)-J,

variable-diversity-joining;

CDR3,

compatibility determining region 3;

MHC,

major histocompatibility complex;

PHA,

phytohemagglutinin