Identification of HLA-A2-restricted CD8(+) cytotoxic T cell responses in primary biliary cirrhosis: T cell activation is augmented by immune complexes cross-presented by dendritic cells.
Primary biliary cirrhosis (PBC) is characterized by an intense biliary inflammatory CD4(+) and CD8(+) T cell response. Very limited information on autoantigen-specific cytotoxic T lymphocyte (CTL) responses is available compared with autoreactive CD4(+) T cell responses. Using peripheral blood mononuclear cells (PBMCs) from PBC, we identified an HLA-A2-restricted CTL epitope of the E2 component of pyruvate dehydrogenase (PDC-E2), the immunodominant mitochondrial autoantigen. This peptide, amino acids 159-167 of PDC-E2, induces specific MHC class I-restricted CD8(+) CTL lines from 10/12 HLA-A2(+) PBC patients, but not controls, after in vitro stimulation with antigen-pulsed dendritic cells (DCs). PDC-E2-specific CTLs could also be generated by pulsing DCs with full-length recombinant PDC-E2 protein. Furthermore, using soluble PDC-E2 complexed with either PDC-E2-specific human monoclonal antibody or affinity-purified autoantibodies against PDC-E2, the generation of PDC-E2-specific CTLs, occurred at 100-fold and 10-fold less concentration, respectively, compared with soluble antigen alone. Collectively, these data demonstrate that autoantibody, helper, and CTL epitopes all contain a shared peptide sequence. The finding that autoantigen-immune complexes can not only cross-present but also that presentation of the autoantigen is of a higher relative efficiency, for the first time defines a unique role for autoantibodies in the pathogenesis of an autoimmune disease.
Kita
Hiroto
H
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA.
Lian
Zhe-Xiong
ZX
Van de Water
Judy
J
He
Xiao-Song
XS
Matsumura
Shuji
S
Kaplan
Marshall
M
Luketic
Velimir
V
Coppel
Ross L
RL
Ansari
Aftab A
AA
Gershwin
M Eric
ME
D017951:Antigen Presentation; D000936:Antigen-Antibody Complex / Q000276:immunology; D015551:Autoimmunity; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D000939:Epitopes; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D009842:Oligopeptides / Q000276:immunology; D011768:Pyruvate Dehydrogenase Complex / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000936:Antigen-Antibody Complex; D016207:Cytokines; D000939:Epitopes; D015789:HLA-A2 Antigen; D009842:Oligopeptides; D011768:Pyruvate Dehydrogenase Complex; D051047:Dihydrolipoyllysine-Residue Acetyltransferase