Death by neglect as a deletional mechanism of peripheral tolerance
Death by neglect as a deletional mechanism of peripheral tolerance
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DOI：
10.1093/intimm/11.8.1225
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发表时间：
1999-08-01
影响因子：
4.4
通讯作者：
Rabourdin-Combe, C
中科院分区：
文献类型：
--
作者：
Bertolino, P;Trescol-Biémont, MC;Rabourdin-Combe, C
与大多数器官不同，肝脏的解剖结构可能允许初始CD8(+) T细胞与肝实质细胞直接接触。我们之前已经证明，使用TCR转基因H-2 K-b的T细胞和表达转基因H-2 K-b分子的肝细胞的组合，肝细胞可以诱导抗原特异性激活和幼稚CD8(+) T细胞的增殖，而不依赖于CD28的共刺激。然而，肝细胞激活T细胞会导致体内和体外的T细胞过早死亡和耐受。在本研究中，我们利用原代肝细胞激活纯化的CD8(+) T细胞，在体外研究了肝细胞诱导T细胞死亡的机制，Fas和肿瘤坏死因子受体均未参与，表明肝细胞诱导的死亡与活化诱导的细胞死亡不同。在开始分裂之前，被肝细胞激活的T细胞表达的bcl-x(L)存活基因水平较低，IL-2 mRNA表达量比被脾抗原呈递细胞激活的CD8（+）细胞少30倍。由于CD28共刺激增加了IL-2和bcl-x(L)表达，这表明肝细胞活化的T细胞因忽视而死亡，因为它们无法接受有效的共刺激信号。与该模型一致，通过交联CD28可以预防肝细胞过早死亡，CD28交联后的存活与IL-2和bcl-x(L)表达的增加以及T细胞的持续增殖相关，而与未共刺激CD28的细胞相比，细胞毒性T淋巴细胞活性延长。本研究证实，高亲和力的TCR转基因抗原特异性CD8(+) T细胞可以被激活增殖并分化为细胞毒性效应细胞。然而，延长T细胞存活和细胞毒性也需要CD28共刺激。据我们所知，这是第一篇报道表明，在缺乏CD28共刺激的情况下，耐受可能是由fas非依赖性外周缺失而不是能量引起的。
In contrast to most organs, the anatomy of the liver may allow naive CD8(+) T cells to make direct contact with liver parenchymal cells. We have previously shown, using a combination of TCR transgenic T cells specific for H-2 K-b and hepatocytes expressing a transgenic H-2 K-b molecule, that hepatocytes can induce antigen-specific activation and proliferation of naive CD8(+) T cells independently of CD28 co-stimulation, However, T cell activation by hepatocytes leads to premature T cell death and tolerance, both in vivo and in vitro. In this study, we investigated the mechanisms of T cell death induced by hepatocytes in vitro using primary hepatocytes to activate purified CD8(+) T cells, Neither Fas nor tumor necrosis factor receptor were involved, indicating that hepatocyte-induced death was distinct from activation-induced cell death. Before they started to divide, T cells activated by hepatocytes expressed lower levels of the bcl-x(L) survival gene and 30 times less IL-2 mRNA than CD8(+) cells activated by splenic antigen-presenting cells, Since CD28 co-stimulation increases both IL-2 and bcl-x(L) expression, this suggests that hepatocyte-activated T cells die by neglect because they fail to receive effective co-stimulatory signals. In agreement with this model, premature death promoted by hepatocytes could be prevented by cross-linking CD28, Survival after CD28 crosslinking correlated with increased IL-2 and bcl-x(L) expression, and sustained T cell proliferation, while cytotoxic T lymphocyte activity was prolonged as compared with cells stimulated without CD28 co-stimulation. This study confirms that high-affinity TCR transgenic antigen-specific CD8(+) T cells can be activated to proliferate and differentiate into cytotoxic effector cells. However, prolonged T cell survival and cytotoxicity required CD28 co-stimulation as well. To our knowledge, this is the first report suggesting that tolerance in the context of lack of CD28 co-stimulation can result from Fas-independent peripheral deletion rather than from anergy.