Distinct Costimulation Dependent and Independent Autoreactive T-Cell Clones in Primary Biliary Cirrhosis

Takashi Kamihira, Shinji Shimoda, Kenichi Harada, Akira Kawano, Mizuki Handa, Eishi Baba, Koichi Tsuneyama, Minoru Nakamura, Hiromi Ishibashi, Yasuni Nakanuma, M. Eric Gershwin, Mine Harada

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Abstract

Background & Aims: Previous work has suggested that CD4+ CD28- or costimulation-independent T cells are increased in autoimmune diseases. In this study, we compared frequency and qualitative characteristics of autoreactive costimulation-independent or CD4+ CD28- T cells in primary biliary cirrhosis (PBC) by taking advantage of the well-defined immunodominant autoepitope of the E2 component of pyruvate dehydrogenase (PDC-E2). Methods: We determined the frequency of costimulation-independent autoreactive T cells that respond to PDC-E2 163-176 and the frequency of CD4+ CD28- T cells. Finally, we determined the role of biliary epithelial cells (BEC) as both an antigen-presenting cell or, alternatively, as a target cell for T-cell-mediated cytotoxicity. Results: The precursor frequency of costimulation-independent CD4+ T cells that respond to PDC-E2 163-176 and the frequency of CD4+ CD28- T cells were dramatically elevated in PBC. Furthermore, 2 types of T-cell clones that respond to PDC-E2 163-176 emerged from this study. One type was costimulation dependent and the other costimulation independent. Both types of clones lyse BEC in a similar effector target (E/T) ratio distribution. However, BEC did not help the proliferation of any T-cell clones. Furthermore, costimulation-independent T-cell clones do not become anergic by BEC. Conclusions: In PBC, costimulation-independent autoreactive T cells, which do not become anergic, increase and maintain the autoimmune response. In controls, although autoantigens are expressed on BEC and autoantigen-reactive T cells exist around BEC, autoantigen-reactive T cells are costimulation dependent and will become anergic and maintain peripheral tolerance.

Original languageEnglish
Pages (from-to)1379-1387
Number of pages9
JournalGastroenterology
Volume125
Issue number5
DOIs
Publication statusPublished - Nov 2003

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

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    Kamihira, T., Shimoda, S., Harada, K., Kawano, A., Handa, M., Baba, E., Tsuneyama, K., Nakamura, M., Ishibashi, H., Nakanuma, Y., Gershwin, M. E., & Harada, M. (2003). Distinct Costimulation Dependent and Independent Autoreactive T-Cell Clones in Primary Biliary Cirrhosis. Gastroenterology, 125(5), 1379-1387. https://doi.org/10.1016/j.gastro.2003.07.013