Autoreactive T-cell responses in primary biliary cirrhosis are proinflammatory whereas those of controls are regulatory.
OBJECTIVE
Autoreactive T cells that proliferate in response to autoantigens are found in both autoimmune disease and controls but have important qualitative differences in relative activation states, costimulation signal requirements, and pathogenetic significance. Understanding the mechanism for activation of autoreactive T cells will be critical in the treatment of autoimmune diseases.


METHODS
To understand the differences between autoreactive T cells in primary biliary cirrhosis (PBC) versus controls, we have developed autoreactive T-cell clones (TCCs) from patients with PBC and healthy controls and have used a peptide corresponding to the CD4 major autoepitope to define the relative proliferative and cytokine response.


RESULTS
Using an enzyme-linked immunosorbent spot assay, peripheral blood mononuclear cells (PBMCs) from PBC, but not from controls, produce interferon (IFN)-gamma regardless of whether costimulation-competent or -incompetent antigen-presenting cells (APC) were used. In contrast, a significant number of IFN-gamma-producing cells were found in PBMCs from controls but only if costimulation-competent PBMCs presented an autoantigenic peptide. In addition, costimulation-dependent autoreactive TCCs became anergic after a single round of stimulation in the presence of APC that did not provide a costimulatory signal, whereas some costimulation-independent autoreactive TCCs required repeated stimulation to become anergic and the others did not become anergic. Finally, anergic TCCs produced interleukin-10, but no IFN-gamma, and exhibited regulatory functions in an antigen-dependent, cell contact-independent, and partially interleukin-10-mediated manner.


CONCLUSIONS
These data relate specifically to the functional characteristics of autoreactive T cells in PBC but are also generically important for understanding the mechanisms for generating pathogenetic autoreactive T cells.
Shimoda
Shinji
S
Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. sshimoda@intmed1.med.kyushu-u.ac.jp
Ishikawa
Fumihiko
F
Kamihira
Takashi
T
Komori
Atsumasa
A
Niiro
Hiroaki
H
Baba
Eishi
E
Harada
Kenichi
K
Isse
Kumiko
K
Nakanuma
Yasuni
Y
Ishibashi
Hiromi
H
Gershwin
M Eric
ME
Harada
Mine
M
D001324:Autoantigens / Q000276:immunology*; D001706:Biopsy; D049109:Cell Proliferation; D002851:Chromatography, High Pressure Liquid; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
D001324:Autoantigens; D024101:Mitochondrial Proteins; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; C494878:Dlat protein, mouse