Peripheral tolerance and the qualitative characteristics of autoreactive T cell clones in primary biliary cirrhosis
Peripheral tolerance and the qualitative characteristics of autoreactive T cell clones in primary biliary cirrhosis
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DOI：
10.4049/jimmunol.179.5.3315
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发表时间：
2007-09-01
影响因子：
4.4
通讯作者：
Harada, Mine
中科院分区：
文献类型：
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作者：
Kawano, Akira;Shimoda, Shinji;Harada, Mine
原发性胆汁性肝硬化的特征在于对线粒体Ag PDC-E2（163-176-）特异性的自身反应性T细胞。我们研究了对PDC-E2（163-176）特异性的8个T细胞克隆（TCC）在共刺激信号存在下增殖或变得无反应性的能力。TCC用人PDC-E2（163-176）、大肠杆菌2-酮戊二酸脱氢酶模拟物（OGDCE 2（34-47））或具有氨基酸取代的类似物刺激，使用HLA匹配的同种异体PBMC或小鼠L-DR 53成纤维细胞作为APC。基于它们对这些肽（人PDC-E2（163-176），E. coliOGDC-E2（34-47））中，TCC分为共刺激依赖型和非共刺激依赖型。只有共刺激依赖的TCC才能成为无反应性的。对OGDGE 2具有共刺激依赖性反应的TCC在与模拟物预孵育时变得对PDGE 2无反应性，即使共刺激不依赖于PDGE 2（163-176），无反应性TCC产生IL-10。一种选择的TCC在与PDC-E2（163-176-）脉冲的L-DR 53预孵育后不能变得无反应性，但使用在关键TCR结合位点处具有取代的PDGE 2肽类似物脉冲的L-DR 53变得无反应性。仅对肽脉冲的PBMC而不是L-DR 53应答的TCC用肽脉冲的CD 80/CD 86转染的L-DR 53增殖;然而，仅用CD 80或CD 86转染的肽脉冲的L-DR 53不诱导无反应性。这些数据强调了共刺激在维持外周对PBMC特异性抗原的耐受性中起主导作用。他们进一步指出，在特定情况下，自身抗原的分子模拟可能恢复而不是破坏外周耐受。
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.