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, Judith A Van de Water, Xiaosong He, Shuji Matsumura, Marshall Kaplan, Velimir Luketic, Ross L. Coppel, Aftab A. Ansari, M. Eric Gershwin

Research output: Contribution to journalArticle

228 Scopus citations

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 (US)
Pages (from-to)113-123
Number of pages11
JournalJournal of Experimental Medicine
Volume195
Issue number1
DOIs
StatePublished - Jan 7 2002

Keywords

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

ASJC Scopus subject areas

  • Immunology

Fingerprint Dive into the research topics of 'Identification of HLA-A2-restricted CD8<sup>+</sup> cytotoxic T cell responses in primary biliary cirrhosis: T cell activation is augmented by immune complexes cross-presented by dendritic cells'. Together they form a unique fingerprint.

  • Cite this