Peripheral tolerance and the qualitative characteristics of autoreactive T cell clones in primary biliary cirrhosis

Akira Kawano, Shinji Shimoda, Takashi Kamihira, Fumihiko Ishikawa, Hiroaki Niiro, Yuji Soejima, Akinobu Taketomi, Yoshihiko Maehara, Minoru Nakamura, Atsumasa Komori, Kiyoshi Migita, Hiromi Ishibashi, Miyuki Azuma, M. Eric Gershwin, Mine Harada

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Primary biliary cirrhosis is characterized by autoreactive T cells specific for the mitochondrial Ag PDC-E2163-176. We studied the ability of eight T cell clones (TCC) specific for PDC-E2163-176 to proliferate or become anergic in the presence of costimulation signals. TCC were stimulated with either human PDC-E2163-176, an Escherichia coli 2-oxoglutarate dehydrogenase mimic (OGDC-E234-47), or analogs with amino acid substitutions using HLA-matched allogeneic PBMC or mouse L-DR53 fibroblasts as APC. Based on their differential responses to these peptides (human PDC-E2 163-176, E. coli OGDC-E234-47) in the different APC systems, TCC were classified as costimulation dependent or independent. Only costimulation-dependent TCC could become anergic. TCC with costimulation- dependent responses to OGDC-E2 become anergic to PDC-E2 when preincubated with mimic, even if costimulation is independent for PDC-E2163-176. Anergic TCC produced IL-10. One selected TCC could not become anergic after preincubation with PDC-E2163-176-pulsed L-DR53 but became anergic using L-DR53 pulsed with PDC-E2 peptide analogs with a substitution at a critical TCR binding site. TCC that only respond to peptide-pulsed PBMC, but not L-DR53, proliferate with peptide-pulsed CD80/CD86-transfected L-DR53; however, anergy was not induced with peptide-pulsed L-DR53 transfected with only CD80 or CD86. These data highlight that costimulation plays a dominant role in maintaining peripheral tolerance to PBC-specific Ags. They further suggest that, under specific circumstances, molecular mimicry of an autoantigen may restore rather than break peripheral tolerance.

Original languageEnglish (US)
Pages (from-to)3315-3324
Number of pages10
JournalJournal of Immunology
Volume179
Issue number5
StatePublished - Sep 1 2007

ASJC Scopus subject areas

  • Immunology

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    Kawano, A., Shimoda, S., Kamihira, T., Ishikawa, F., Niiro, H., Soejima, Y., Taketomi, A., Maehara, Y., Nakamura, M., Komori, A., Migita, K., Ishibashi, H., Azuma, M., Gershwin, M. E., & Harada, M. (2007). Peripheral tolerance and the qualitative characteristics of autoreactive T cell clones in primary biliary cirrhosis. Journal of Immunology, 179(5), 3315-3324.