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

Hiroto Kita, Zhe Xiong Lian, Judy Van De Water, Xiao Song He, Shuji Matsumura, Marshall Kaplan, Velimir Luketic, Ross L. Coppel, Aftab A. Ansari, M. Eric Gershwin

Research output: Contribution to journalArticleResearchpeer-review

228 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)113-123
Number of pages11
JournalJournal of Experimental Medicine
Volume195
Issue number1
DOIs
Publication statusPublished - 7 Jan 2002

Keywords

  • Autoimmunity
  • Cholangitis
  • Cross-priming
  • Cytotoxic T cells
  • Epitopes

Cite this