Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis.
While the pathologic mechanisms responsible for organ-specific tissue damage in primary biliary cirrhosis (PBC) remain an enigma, it has been suggested that the pathology is mediated by autoreactive T cells infiltrating the intrahepatic bile ducts. Previously, we have documented that there is 100-fold enrichment in the frequency of CD4(+) autoreactive T cells in the liver that are specific for peptides encoded by the E2 components of the pyruvate dehydrogenase complexes (PDC-E2). We have also recently characterized the first MHC class I-restricted epitope for PDC-E2, namely amino acid 159-167, a region very similar to the epitope recognized by MHC class II-restricted CD4(+) cells and by autoantibodies. The effector functions of these PDC-E2(159-167)-specific CD8(+) cytotoxic T lymphocytes (CTLs) are not well understood. We have taken advantage of tetramer technology and report herein that there is tenfold increase in the frequency of PDC-E2(159-167)-specific CTLs in the liver as compared with the blood in PBC. In addition, the precursor frequency of the CTLs in blood was significantly higher in early-stage PBC. Of interest was the fact that, upon stimulation with the peptide, the response of PDC-E2(159-167) tetramer-positive cells is heterogeneous with respect to IFN-gamma synthesis. These data, we believe for the first time, document the enrichment of autoantigen-specific CD8(+) T cells in the PBC liver, suggesting that CD8(+) T cells play a significant role in the immunopathogenesis of PBC.
Kita
Hiroto
H
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, California 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
D001324:Autoantigens / Q000276:immunology*; D002478:Cells, Cultured; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D000939:Epitopes / Q000276:immunology; D005434:Flow Cytometry; D015234:HLA-A Antigens / Q000276:immunology; D015789:HLA-A2 Antigen; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008099:Liver / Q000276:immunology; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D011768:Pyruvate Dehydrogenase Complex / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D001324:Autoantigens; D000939:Epitopes; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D011768:Pyruvate Dehydrogenase Complex; D007371:Interferon-gamma; D051047:Dihydrolipoyllysine-Residue Acetyltransferase