Analysis of TCR antagonism and molecular mimicry of an HLA-A*0201-restricted CTL epitope in primary biliary cirrhosis

Hiroto Kita, Shuji Matsumura, Xiaosong He, Aftab A. Ansari, Zhe Xiong Lian, Judith A Van de Water, Ross L. Coppel, Marshall M. Kaplan, M. Eric Gershwin

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Althoug the etiology and mechanism of primary biliary cirrhosis (PBC) is unknown, growing evidence suggests a major role for T cells. We have recently identified the first CD8 T-cell epitope, amino acid 159-167 of the E2 component of pyruvate dehydrogenase complexes (PDC-E2). To seek for analogue peptide-antagonizing effector function of CTLs specific for this autoantigen, we examined the effector functions of the PDC-E2-specific CTLs against alanine substituted peptides. Furthermore, because molecular mimicry has been postulated as a possible cause of initiating PBC, we carried out studies aimed at identifying naturally occurring peptides for the 159-167 peptide of PDC-E2 that may serve as agonists. An alanine substitution at position 5 of this epitope significantly reduced peptide-specific effector functions of CTLs. Moreover, this analogue peptide inhibited effector functions of the CTLs to the prototype peptide, including cytotoxicity and IFN-τ production. We also identified a peptide derived from Pseudomonas aeruginosa, which showed a higher binding affinity to the HLA-A*0201 than the prototype peptide. This homologous peptide was recognized by CTLs specific for the prototype epitope on PDC-E2. In conclusion, a modification of the immunodominant autoepitope can be utilized to manipulate the CD8 T-cell responses against the autoantigen PDC-E2. Our finding also supports the thesis that molecular mimicry may be implicated in the initiation of the autoreactive CD8 T-cell responses and has implications for the use of such peptides for immunotherapy.

Original languageEnglish (US)
Pages (from-to)918-926
Number of pages9
JournalHepatology
Volume36
Issue number4 I
DOIs
StatePublished - Oct 1 2002

ASJC Scopus subject areas

  • Hepatology

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