Distinct costimulation dependent and independent autoreactive T-cell clones in primary biliary cirrhosis.
OBJECTIVE
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.
Kamihira
Takashi
T
Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-101 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
Shimoda
Shinji
S
Harada
Kenichi
K
Kawano
Akira
A
Handa
Mizuki
M
Baba
Eishi
E
Tsuneyama
Koichi
K
Nakamura
Minoru
M
Ishibashi
Hiromi
H
Nakanuma
Yasuni
Y
Gershwin
M Eric
ME
Harada
Mine
M
D000938:Antigen-Presenting Cells / Q000473:pathology; D015551:Autoimmunity; D001652:Bile Ducts / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D017635:Clonal Anergy; D002999:Clone Cells / Q000276:immunology*; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000276:immunology* / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology; D011768:Pyruvate Dehydrogenase Complex / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*
D010446:Peptide Fragments; D011768:Pyruvate Dehydrogenase Complex; D051047:Dihydrolipoyllysine-Residue Acetyltransferase