Interleukin-2, a pro-autoimmune lymphokine that interferes with post-deletional tolerance.
Interleukin-2, a pro-autoimmune lymphokine that interferes with post-deletional tolerance.
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Interleukin-2，一种干扰删除后耐受性的促自身免疫性淋巴因子。
作者：
G. Kroemer;C. Martínez
以自动防故障等级排列的各种互补机制阻止免疫系统发起自身攻击，即胸腺内或胸腺后克隆删除、无反应性和免疫抑制。流行病学和临床证据均表明白介素 2 (IL-2) 可能发挥促自身免疫作用。因此，IL-2在确定的体外或体内环境下逆转免疫耐受，在某些自身免疫性疾病中以异常高的水平产生，并且当给予患者时诱导器官特异性自身免疫损伤。为了阐明负责 IL-2 促自身免疫性质的分子和细胞机制，我们的小组采用了重组 hIL-2 痘苗病毒构建体 (IL-2.VV) 作为自我复制的 IL-2 释放装置，可以作为外源性 IL-2 的来源给予实验操作的小鼠。自应用 IL-2 以来，IL-2 不会干扰胸腺中潜在自身反应性 T 细胞的克隆删除。对年轻小鼠进行 VV 治疗无法增加携带“禁止”T 细胞受体 (TCR) V beta 基因产物的 T 细胞（即识别内源性逆转录病毒超抗原的 T 细胞）的频率。沿着同一条线，IL-2。 VV 不会逆转携带雄性特异性转基因 α/β TCR 且经历 CD4+ CD8+ 胸腺细胞耗竭的雄性小鼠的克隆缺失，也不会消除与细菌超抗原金黄色葡萄球菌肠毒素 B (SEB) 反应的 V beta 8+ T 细胞的胸腺后克隆缺失。与它无法以无根据的特异性消除胸腺内和胸腺后 T 细胞的消除相反，IL-2 消除了 T 细胞的无反应性。来自先天性无胸腺或新生胸腺切除小鼠的未删除、“禁止”T 细胞在正常情况下无活性，会对 TCR 触发产生反应，并介导 IL-2 引起的全身性自身免疫综合征。 VV治疗。因此，IL-2 似乎会在删除后阶段干扰 T 细胞耐受性，逆转功能性无反应性，并使具有潜在自身反应性 TCR 库的未删除 T 细胞能够引起明显的自身免疫。
Various complementary mechanisms arranged in a fail-safe hierarchy impede the immune system from launching auto-aggressive attacks, namely intrathymic or post-thymic clonal deletion, anergy, and immunosuppression. Both epidemiological and clinical evidence demonstrates that interleukin-2 (IL-2) may exert a pro-autoimmune effect. Thus, IL-2 reverses immunological tolerance in determined in vitro or in vivo circumstances, is produced at abnormally high levels in certain autoimmune diseases, and induces organ-specific autoimmune lesions when administered to patients. To unravel the molecule and cellular mechanisms responsible for the pro-autoimmune nature of IL-2, our group has employed a recombinant hIL-2 vaccinia virus construct (IL-2. VV) as a self-replicating IL-2-releasing device that may be administered as a source of exogenous IL-2 to experimentally manipulated mice. IL-2 does not interfere with clonal deletion of potentially autoreactive T cells in the thymus since application of IL-2. VV to young mice fails to augment the frequency of T cells bearing 'forbidden' T cell receptor (TCR) V beta gene products (i.e. T cells that recognize endogenous retroviral superantigens). Along the same line, IL-2. VV does not reverse the clonal deletion in male mice bearing a male-specific transgenic alpha/beta TCR that undergo depletion of CD4+ CD8+ thymocytes, nor does it abolish post-thymic clonal deletion of V beta 8+ T cells reactive with the bacterial superantigen Staphylococcus aureus enterotoxin B (SEB). In contrast with its incapability to abolish intra- and post-thymic elimination of T cells with unwarranted specificities, IL-2 abrogates anergy of T cells. Non-deleted, 'forbidden' T cells from congenitally athymic or neonatally thymectomized mice, under normal circumstances anergic, become responsive to TCR-triggering and mediate a systemic autoimmune syndrome upon IL-2. VV treatment. Thus, IL-2 appears to interfere with T cell tolerance at a post-deletional stage, reversing functional non-responsiveness and enabling non-deleted T cells that bear a potentially autoreactive TCR repertoire to cause manifest autoimmunity.