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 (OGDCE2(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 OGDGE2 become anergic to PDGE2 when preincubated with mimic, even if costimulation is independent for PDGE2(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 PDGE2 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 PBCspecific Ags. They further suggest that, under specific circumstances, molecular mimicry of an autoantigen.may restore rather than break peripheral tolerance.