Analysis of T-cell receptor beta of the T-cell clones reactive to the human PDC-E2 163-176 peptide in the context of HLA-DR53 in patients with primary biliary cirrhosis.
T-cell-mediated autoimmune mechanisms are considered to be involved in the pathogenesis of primary biliary cirrhosis (PBC). In the previous study, we identified the immunodominant T-cell epitope on the E2 component of pyruvate dehydrogenase complex (PDC-E2) in patients with PBC who have HLA-DRB4*0101. In this report, we revealed that the frequency of the T cells reactive to the human PDC-E2 163-176 peptide is significantly increased in the peripheral blood of patients with PBC as compared with healthy subjects. We also confirmed that these T cells were all restricted with HLA-DRB4*01 (DR53) by using HLA-DR-transfected L cells. These results together with the evidence that the immunodominant B-cell epitope overlaps with the human T-cell epitope of the PDC-E2 antigen indicate that the T cells reactive to this epitope are closely associated with the pathogenesis of PBC at least in patients who have HLA-DR53. Therefore, we analyzed the T-cell receptor (TCR) Vbeta sequence of the five different T-cell clones and the three T-cell clones derived from three patients with PBC and healthy subjects, respectively, which are reactive to the human PDC-E2 163-176 peptide in the context of HLA-DR53. The Vbeta- and the Jbeta-gene usages were diverse among the T-cell clones (Vbeta11-Jbeta1.4, Vbeta8-Jbeta1.2, Vbeta12-Jbeta2.1, Vbeta10-Jbeta1.5, and Vbeta20-Jbeta2.1) in patients with PBC. By contrast, in the third complementarity determining region (CDR3), G was frequently found and GXG or GXS motif was identified in all T-cell clones. Moreover, RGXG motif was found in three clones generated from two patients. In healthy subjects, the Vbeta- and the Jbeta-gene usages were also diverse, and GXG and RGXG motif were found. These results indicate that the T cells may recognize the ligand (the human PDC-E2 163-176 peptide/HLA-DR53 complex) using the limited motif in the CDR3 region and that the design of CDR3-specific immunotherapy would be possible using these motifs.
Ichiki
Y
Y
The First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Shimoda
S
S
Hara
H
H
Shigematsu
H
H
Nakamura
M
M
Hayashida
K
K
Ishibashi
H
H
Niho
Y
Y
D000595:Amino Acid Sequence; D017931:DNA Primers; D006684:HLA-DR Antigens / Q000276:immunology*; D059845:HLA-DRB4 Chains; D008105:Liver Cirrhosis, Biliary / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D010446:Peptide Fragments / Q000276:immunology*; D016133:Polymerase Chain Reaction / Q000379:methods; D011768:Pyruvate Dehydrogenase Complex / Q000737:chemistry / Q000276:immunology*; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000276:immunology*
D017931:DNA Primers; D006684:HLA-DR Antigens; C050610:HLA-DR53; D059845:HLA-DRB4 Chains; D015345:Oligonucleotide Probes; D010446:Peptide Fragments; D011768:Pyruvate Dehydrogenase Complex; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta