Peripheral tolerance and the qualitative characteristics of autoreactive T cell clones in primary biliary cirrhosis.
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.
Kawano
Akira
A
Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Shimoda
Shinji
S
Kamihira
Takashi
T
Ishikawa
Fumihiko
F
Niiro
Hiroaki
H
Soejima
Yuji
Y
Taketomi
Akinobu
A
Maehara
Yoshihiko
Y
Nakamura
Minoru
M
Komori
Atsumasa
A
Migita
Kiyoshi
K
Ishibashi
Hiromi
H
Azuma
Miyuki
M
Gershwin
M Eric
ME
Harada
Mine
M
D000217:Acyltransferases / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen / Q000276:immunology; D049109:Cell Proliferation; D017635:Clonal Anergy / Q000276:immunology*; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D006684:HLA-DR Antigens / Q000276:immunology; D059845:HLA-DRB4 Chains; D006801:Humans; D007108:Immune Tolerance; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D001324:Autoantigens; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D016207:Cytokines; D029968:Escherichia coli Proteins; D006684:HLA-DR Antigens; C050610:HLA-DR53; D059845:HLA-DRB4 Chains; D010455:Peptides; D000217:Acyltransferases; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; C021515:dihydrolipoamide succinyltransferase