Comprehensive mapping of HLA-A*0201 - Restricted CD8 T-cell epitopes on PDC-E2 in primary biliary cirrhosis

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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1125-1134
Number of pages10
JournalHepatology
Volume36
Issue number5 II
DOIs
StatePublished - Nov 1 2002

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T-Lymphocyte Epitopes
Biliary Liver Cirrhosis
Peptides
Cytotoxic T-Lymphocytes
Epitopes
Major Histocompatibility Complex
Dihydrolipoyllysine-Residue Acetyltransferase
HLA-A*02:01 antigen
Amino Acids
Peptide Library
Ligands
T-Lymphocytes
Antigens
Cell Line

ASJC Scopus subject areas

  • Hepatology

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Comprehensive mapping of HLA-A*0201 - Restricted CD8 T-cell epitopes on PDC-E2 in primary biliary cirrhosis. / Matsumura, Shuji; Kita, Hiroto; He, Xiaosong; Ansari, Aftab A.; Lian, Zhe Xiong; Van de Water, Judith A; Yamamoto, Kazuhide; Tsuji, Takao; Coppel, Ross L.; Kaplan, Marshall; Gershwin, M. Eric.

In: Hepatology, Vol. 36, No. 5 II, 01.11.2002, p. 1125-1134.

Research output: Contribution to journalArticle

Matsumura, S, Kita, H, He, X, Ansari, AA, Lian, ZX, Van de Water, JA, Yamamoto, K, Tsuji, T, Coppel, RL, Kaplan, M & Gershwin, ME 2002, 'Comprehensive mapping of HLA-A*0201 - Restricted CD8 T-cell epitopes on PDC-E2 in primary biliary cirrhosis', Hepatology, vol. 36, no. 5 II, pp. 1125-1134. https://doi.org/10.1053/jhep.2002.36161
Matsumura, Shuji ; Kita, Hiroto ; He, Xiaosong ; Ansari, Aftab A. ; Lian, Zhe Xiong ; Van de Water, Judith A ; Yamamoto, Kazuhide ; Tsuji, Takao ; Coppel, Ross L. ; Kaplan, Marshall ; Gershwin, M. Eric. / Comprehensive mapping of HLA-A*0201 - Restricted CD8 T-cell epitopes on PDC-E2 in primary biliary cirrhosis. In: Hepatology. 2002 ; Vol. 36, No. 5 II. pp. 1125-1134.
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AU - Matsumura, Shuji

AU - Kita, Hiroto

AU - He, Xiaosong

AU - Ansari, Aftab A.

AU - Lian, Zhe Xiong

AU - Van de Water, Judith A

AU - Yamamoto, Kazuhide

AU - Tsuji, Takao

AU - Coppel, Ross L.

AU - Kaplan, Marshall

AU - Gershwin, M. Eric

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AB - 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.

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