CTLs respond with activation and granule secretion when serving as targets for T-cell recognition
CTLs respond with activation and granule secretion when serving as targets for T-cell recognition
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DOI：
10.1182/blood-2010-05-283770
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发表时间：
2011-01-20
期刊：
影响因子：
20.3
通讯作者：
Reisner, Yair
中科院分区：
文献类型：
--
作者：
Milstein, Oren;Hagin, David;Reisner, Yair
细胞毒性T淋巴细胞（CTL）抑制针对其抗原的T细胞应答，而不管其自身的T细胞受体（TCR）特异性如何。这使得CTL在自身免疫和移植中有希望用于耐受诱导。已经确定，必须允许CTL CD 8分子与识别T细胞的主要组织相容性复合体（MHC）I类α 3结构域结合，以使后者细胞死亡。然而，在没有TCR识别的情况下，由这种分子相互作用在CTL中触发的信号传导事件从未被阐明。在这里，我们使用单细胞成像来研究CTL中发生的事件，CTL作为特定T细胞识别的靶点。我们证明了CTL通过将其细胞毒性颗粒极化到接触区域，释放其致命货物并大力增殖来积极响应识别。使用来自穿孔素敲除（KO）小鼠的CTL和用特异性小干扰RNA（siRNA）敲低的淋巴细胞特异性激酶（Lck），我们表明识别CD 8 T细胞的杀伤是穿孔素依赖的，并且由CTL中的Lck信号启动。总的来说，这些数据表明了一种新的机制，其中通常由TCR接合触发的整个级联在作为T细胞识别的靶标的CTL中被“劫持”，而没有TCR连接。（血。2011; 117（3）：1042-1052）
Cytotoxic T lymphocytes (CTLs) suppress T cell responses directed against their antigens regardless of their own T cell receptor (TCR) specificity. This makes the use of CTLs promising for tolerance induction in autoimmunity and transplantation. It has been established that binding of the CTL CD8 molecule to the major histocompatibility complex (MHC) class I alpha 3 domain of the recognizing T cell must be permitted for death of the latter cell to ensue. However, the signaling events triggered in the CTL by this molecular interaction in the absence of TCR recognition have never been clarified. Here we use single-cell imaging to study the events occurring in CTLs serving as targets for recognition by specific T cells. We demonstrate that CTLs actively respond to recognition by polarizing their cytotoxic granules to the contact area, releasing their lethal cargo, and vigorously proliferating. Using CTLs from perforin knockout (KO) mice and lymphocyte specific kinase (Lck) knockdown with specific small interfering RNA (siRNA), we show that the killing of the recognizing CD8 T cell is perforin dependent and is initiated by Lck signaling in the CTL. Collectively, these data suggest a novel mechanism in which the entire cascade generally triggered by TCR engagement is "hijacked" in CTLs serving as targets for T cell recognition without TCR ligation. (Blood. 2011; 117(3): 1042-1052)