Analysis of TCR antagonism and molecular mimicry of an HLA-A0201-restricted CTL epitope in primary biliary cirrhosis.
Although 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-gamma 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.
Kita
Hiroto
H
Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, 95616, USA.
Matsumura
Shuji
S
He
Xiao-Song
XS
Ansari
Aftab A
AA
Lian
Zhe-Xiong
ZX
Van de Water
Judy
J
Coppel
Ross L
RL
Kaplan
Marshall M
MM
Gershwin
M Eric
ME
D001426:Bacterial Proteins / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000166:cytology / Q000276:immunology; D002460:Cell Line; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D015234:HLA-A Antigens / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D018716:Molecular Mimicry / Q000276:immunology*; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011550:Pseudomonas aeruginosa / Q000737:chemistry; D011768:Pyruvate Dehydrogenase Complex / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000737:chemistry* / Q000166:cytology / Q000276:immunology
D001426:Bacterial Proteins; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D011768:Pyruvate Dehydrogenase Complex; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma; D051047:Dihydrolipoyllysine-Residue Acetyltransferase