Autoreactive T-cell responses in primary biliary cirrhosis are proinflammatory whereas those of controls are regulatory
Autoreactive T-cell responses in primary biliary cirrhosis are proinflammatory whereas those of controls are regulatory
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DOI：
10.1053/j.gastro.2006.05.056
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发表时间：
2006-08-01
期刊：
影响因子：
29.4
通讯作者：
Harada, Mine
中科院分区：
文献类型：
--
作者：
Shimoda, Shinji;Ishikawa, Fumihiko;Harada, Mine
背景和目标：在自身免疫性疾病和对照中均发现自身反应性T细胞，其响应于自身抗原而增殖，但在相对活化状态、共刺激信号要求和致病意义方面具有重要的质的差异。了解自身反应性T细胞活化的机制将是治疗自身免疫性疾病的关键。研究方法：为了了解原发性胆汁性肝硬化（PBC）与对照组自身反应性T细胞之间的差异，我们从PBC患者和健康对照组中开发了自身反应性T细胞克隆（TCC），并使用了与CD 4主要自身表位对应的肽来定义相对增殖和细胞因子应答。结果如下：使用酶联免疫吸附斑点试验，外周血单个核细胞（PBMC）从PBC，但不是从控制，产生干扰素（IFN）-γ，无论是否共刺激能力或无能的抗原呈递细胞（APC）被使用。与此相反，大量的IFN-γ产生细胞被发现在PBMC中的控制，但只有当共刺激能力的PBMC提出了一个自身抗原肽。此外，共刺激依赖性自身反应性TCC在不提供共刺激信号的APC存在下的单轮刺激后变得无反应性，而一些共刺激非依赖性自身反应性TCC需要重复刺激才能变得无反应性，而其他的没有变得无反应性。最后，无反应性TCC产生白细胞介素-10，但没有IFN-γ，并表现出抗原依赖性，细胞接触无关性和部分白细胞介素-10介导的方式的调节功能。结论：这些数据具体涉及PBC中自身反应性T细胞的功能特征，但对于理解产生致病性自身反应性T细胞的机制也具有普遍重要性。
Background & Aims: 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 auto-epitope 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.