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Peripheral Tolerance and the Qualitative Characteristics of Autoreactive T Cell Clones in Primary Biliary Cirrhosis¹

Akira Kawano^*, Shinji Shimoda^2,*, 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^# and Mine Harada^*

^* Medicine and Biosystemic Science and Department of Surgery and Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Research Unit for Human Disease Model, RIKEN Center for Allergy and Immunology, Yokohama, Japan; Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan; ^¶ National Nagasaki Medical Center, Omura, Japan; ^|| Department of Molecular Immunology, Tokyo Medical and Dental University, Tokyo, Japan; and ^# Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, University of California, Davis, CA 95616

Primary biliary cirrhosis is characterized by autoreactive T cells specific for the mitochondrial Ag PDC-E2_163–176. We studied the ability of eight T cell clones (TCC) specific for PDC-E2_163–176 to proliferate or become anergic in the presence of costimulation signals. TCC were stimulated with either human PDC-E2_163–176, an Escherichia coli 2-oxoglutarate dehydrogenase mimic (OGDC-E2_34–47), 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-E2_34–47) 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-E2_163–176. Anergic TCC produced IL-10. One selected TCC could not become anergic after preincubation with PDC-E2_163–176-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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was partly supported by Grant-in-Aid 17590657 for Scientific Research (C) of Japan and National Institutes of Health Grant DK39588.

² Address correspondence and reprint requests to Dr. Shinji Shimoda, Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. E-mail address: sshimoda{at}intmed1.med.kyushu-u.ac.jp

³ Abbreviations used in this paper: PBC, primary biliary cirrhosis; Treg, regulatory T cell; PDCpep, human PDC-E2_163–176 peptide; OGDCpep, E. coli OGDC-E2_34–37 peptide.