Fine specificity of T cells reactive to human PDC-E2 163-176 peptide, the immunodominant autoantigen in primary biliary cirrhosis: implications for molecular mimicry and cross-recognition among mitochondrial autoantigens.
The anti-mitochondrial antibody response in primary biliary cirrhosis (PBC) is primarily directed at E2 components of PDC, OGDC, and BCOADC, and E3BP. Previous work has shown that the immunodominant autoreactive T- cell epitope is the PDC-E2 163-176 peptide, restricted by HLA DR53. To address molecular mimicry and cross-recognition among mitochondrial autoantigens, we analyzed reactivity, including agonism and antagonism assays, to a series of single amino acid-substituted peptides using cloned T-cell lines in PBC and controls. Interestingly, fine specificities were unique for every single T-cell clone, but the clones could be categorized into two distinct groups based on recognition motifs of the T-cell receptor (TCR) ligand: group A (170)ExDK(173) and group B (168)EIExD(172). (170)E is the most critical TCR contact residue for both groups of cloned T-cell lines, whereas (173)K and (168)E are the critical TCR contact residues for group A and group B cloned T-cell lines, respectively. More importantly, some group A-cloned T-cell lines cross-reacted to human E3BP 34-47, human OGDC-E2 100-113, and several peptides derived from various microbial proteins carrying an ExDK motif, whereas group B-cloned T-cell lines reacted only to E3BP 34-47 carrying an EIExD motif. Furthermore, an RGxG motif was exclusively found in the complementarity-determining region (CDR3) of the TCR Vbeta in the group B-cloned T-cell lines, while G, S, and/or R were frequently found in the CDR3 of the TCR Vbeta in the group A-cloned T-cell lines. These data provide a framework for understanding molecular mimicry among mitochondrial antigens.
Shigematsu
H
H
The First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Shimoda
S
S
Nakamura
M
M
Matsushita
S
S
Nishimura
Y
Y
Sakamoto
N
N
Ichiki
Y
Y
Niho
Y
Y
Gershwin
M E
ME
Ishibashi
H
H
D000595:Amino Acid Sequence / Q000235:genetics; D019943:Amino Acid Substitution; D000918:Antibody Specificity; D001324:Autoantigens / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D003429:Cross Reactions; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D000939:Epitopes; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D008928:Mitochondria / Q000276:immunology*; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D011768:Pyruvate Dehydrogenase Complex / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D001324:Autoantigens; D000939:Epitopes; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D011768:Pyruvate Dehydrogenase Complex; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051047:Dihydrolipoyllysine-Residue Acetyltransferase