Peripheral Tolerance and the Qualitative Characteristics of Autoreactive T Cell Clones in Primary Biliary Cirrhosis
| Autor: | M. Eric Gershwin, Mine Harada, Hiromi Ishibashi, Yoshihiko Maehara, Kiyoshi Migita, Akira Kawano, Atsumasa Komori, Hiroaki Niiro, Fumihiko Ishikawa, Minoru Nakamura, Shinji Shimoda, Takashi Kamihira, Miyuki Azuma, Yuji Soejima, Akinobu Taketomi |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
T-Lymphocytes
T cell Immunology Antigen-Presenting Cells Biology Dihydrolipoyllysine-Residue Acetyltransferase Lymphocyte Activation medicine.disease_cause Autoantigens Immune tolerance Mice Immune Tolerance medicine Animals Humans Immunology and Allergy Antigen-presenting cell Cell Proliferation Clonal Anergy CD86 Clonal anergy Liver Cirrhosis Biliary Escherichia coli Proteins Peripheral tolerance hemic and immune systems HLA-DR Antigens Fibroblasts Coculture Techniques Molecular mimicry medicine.anatomical_structure B7-1 Antigen Cytokines B7-2 Antigen Peptides Acyltransferases HLA-DRB4 Chains CD80 |
| Zdroj: | The Journal of Immunology. 179:3315-3324 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.179.5.3315 |
| Popis: | Primary biliary cirrhosis is characterized by autoreactive T cells specific for the mitochondrial Ag PDC-E2163–176. We studied the ability of eight T cell clones (TCC) specific for PDC-E2163–176 to proliferate or become anergic in the presence of costimulation signals. TCC were stimulated with either human PDC-E2163–176, an Escherichia coli 2-oxoglutarate dehydrogenase mimic (OGDC-E234–47), 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-E2163–176, E. coli OGDC-E234–47) 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-E2163–176. Anergic TCC produced IL-10. One selected TCC could not become anergic after preincubation with PDC-E2163–176-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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|