S.M. and H.K. contributed equally to this work.
Comprehensive mapping of HLA-A*0201–restricted CD8 T-cell epitopes on PDC-E2 in primary biliary cirrhosis
Article first published online: 30 DEC 2003
Copyright © 2002 American Association for the Study of Liver Diseases
Volume 36, Issue 5, pages 1125–1134, November 2002
How to Cite
Matsumura, S., Kita, H., He, X.-S., Ansari, A. A., Lian, Z.-X., van de Water, J., Yamamoto, K., Tsuji, T., Coppel, R. L., Kaplan, M. and Gershwin, M. E. (2002), Comprehensive mapping of HLA-A*0201–restricted CD8 T-cell epitopes on PDC-E2 in primary biliary cirrhosis. Hepatology, 36: 1125–1134. doi: 10.1053/jhep.2002.36161
- Issue published online: 30 DEC 2003
- Article first published online: 30 DEC 2003
- Manuscript Accepted: 22 JUL 2002
- Manuscript Received: 25 MAR 2002
- National Institutes of Health. Grant Number: DK39588
Growing evidence has implicated the involvement of autoreactive T lymphocytes in the pathogenesis of primary biliary cirrhosis (PBC). We have recently taken advantage of motif prediction analysis of HLA-A*0201 and identified the first major histocompatibility complex (MHC) class I restricted epitope, amino acids 159 to 167 on E2 components of pyruvate dehydrogenase complexes (PDC-E2), the major mitochondrial antigens in PBC. The mechanisms involved in the selection of epitope peptide(s) that comprise the PDC-E2–specific autoreactive cytotoxic T lymphocytes (CTLs) are unknown and likely involve other epitopes on PDC-E2 restricted by MHC class I molecules. To address this issue, a comprehensive mapping of the CTL epitope repertoire on the PDC-E2 molecule that binds HLA-A*0201 was performed to provide further clues regarding the role of CTLs. We used the T2 cell line to screen 79 overlapping 15mer peptides, spanning the entire PDC-E2 molecule. Six of the 79 peptides exhibited significantly higher binding activity to HLA-A*0201 than the other 15mer peptides. Two of these 6 peptides induced CTL lines from patients with PBC. Fine mapping with N-terminus or C-terminus truncated peptides identified 10mer peptide, PDC-E2 amino acids 165 to 174, which is a novel CD8 epitope restricted by HLA-A*0201. In conclusion, using a combination of the 15mer peptide library screening with the T2 binding assay and also the induction of CTL lines with candidate peptides, we have defined a novel HLA-A*0201–restricted epitope PDC-E2 165 to 174 in patients with PBC. These data will become important in the development of altered peptide ligands to modulate disease activity.