Activation of T cells recognizing self 60-kD heat shock protein can protect against experimental arthritis.
Activation of T cells recognizing self 60-kD heat shock protein can protect against experimental arthritis.
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DOI：
10.1084/jem.181.3.943
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发表时间：
1995-03-01
期刊：
影响因子：
--
通讯作者：
van Eden W
中科院分区：
文献类型：
--
作者：
Anderton SM;van der Zee R;Prakken B;Noordzij A;van Eden W
Lewis 大鼠对使用热灭活的结核分枝杆菌（佐剂性关节炎或 AA）、链球菌细胞壁、II 型胶原蛋白和类脂胺 CP20961 诱导的几种形式的实验性关节炎敏感。据报道，预先使用分枝杆菌 65-kD 热休克蛋白 (hsp65) 进行免疫可以通过 T 细胞介导的机制预防 AA 和其他不使用结核分枝杆菌的关节炎模型。 Hsp65 与哺乳动物 hsp60 有 48% 的氨基酸同一性，后者在发炎的滑液中表达水平升高。几项研究报告了关节炎和正常个体中分枝杆菌 hsp65 和自身 hsp60 的交叉反应性 T 细胞识别。我们之前描述了Lewis大鼠T细胞识别的分枝杆菌hsp65中的九个主要组织相容性复合体II类限制性表位。其中只有一个覆盖 256-270 序列，为对大鼠 hsp60 相应区域的交叉反应性 T 细胞反应做好准备。在这里，我们通过用合成肽免疫大鼠来测试每个 hsp65 表位的保护活性。含有 256-270 表位的肽可诱导 T 细胞交叉反应，是唯一能够提供抗 AA 保护的肽。类似地，施用对该表位具有特异性的 T 细胞系可以预防 AA。用256-270表位预免疫诱导T细胞对热休克的同源抗原呈递细胞作出反应，并且还可以防止CP20961诱导的关节炎，表明T细胞的激活、识别自身hsp60中的表位可以防止在没有分枝杆菌的情况下诱导的关节炎。因此，与外来和自身抗原的交叉反应性 T 细胞识别可能诱发侵袭性自身免疫性疾病这一公认概念相反，我们提出细菌和自身 hsp60 之间的交叉反应也可用于维持保护性自身反应性 T 细胞群。这一发现可能对于理解 T 细胞介导的炎症调节具有重要意义。
Lewis rats are susceptible to several forms of experimental arthritis- induced using heat-killed Mycobacterium tuberculosis (adjuvant arthritis, or AA), streptococcal cell walls, collagen type II, and the lipoidal amine CP20961. Prior immunization with the mycobacterial 65-kD heat shock protein (hsp65) was reported to protect against AA, and other athritis models not using M. tuberculosis, via a T cell-mediated mechanism. Hsp65 shares 48% amino acid identity with mammalian hsp60, which is expressed at elevated levels in inflamed synovia. Several studies have reported cross-reactive T cell recognition of mycobacterial hsp65 and self hsp60 in arthritic and normal individuals. We previously described nine major histocompatibility complex class II- restricted epitopes in mycobacterial hsp65 recognized by Lewis rat T cells. Of these only one, covering the 256-270 sequence, primed for cross-reactive T cell responses to the corresponding region of rat hsp60. Here we have tested each hsp65 epitope for protective activity by immunizing rats with synthetic peptides. A peptide containing the 256-270 epitope, which induced cross-reactive T cells, was the only one able to confer protection against AA. Similarly, administration of a T cell line specific for this epitope protected against AA. Preimmunization with the 256-270 epitope induced T cells that responded to heat-shocked syngeneic antigen-presenting cells, and also protected against CP20961-induced arthritis, indicating that activation of T cells, recognizing an epitope in self hsp60 can protect against arthritis induced without mycobacteria. Therefore, in contrast to the accepted concept that cross-reactive T cell recognition of foreign and self antigens might induce aggressive autoimmune disease, we propose that cross-reactivity between bacterial and self hsp60 might also be used to maintain a protective self-reactive T cell population. This discovery might have important implications for understanding T cell- mediated regulation of inflammation.