Signal integration by Akt regulates CD8 T cell effector and memory differentiation.
Signal integration by Akt regulates CD8 T cell effector and memory differentiation.
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DOI：
10.4049/jimmunol.1103568
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发表时间：
2012-05-01
期刊：
影响因子：
--
通讯作者：
Suresh M
中科院分区：
文献类型：
--
作者：
Kim EH;Sullivan JA;Plisch EH;Tejera MM;Jatzek A;Choi KY;Suresh M
在T细胞应答过程中，效应CTL池包含两个细胞亚群：短命效应细胞（SLECs）和记忆前体效应细胞（MPECs），前者大部分最终凋亡，后者分化为记忆细胞。了解控制记忆性CD8 T细胞分化的机制对于开发有效的CD8 T细胞疫苗至关重要。TCR信号的强度和性质以及IL-2和il -12等细胞因子传递的信号影响SLECs和mpec的分化。一个核心问题是，来自多个受体的信号如何被整合和解释以定义效应ctl的命运？利用遗传学和药理学工具，我们发现Akt是一个信号整合者，它将CTL分化的不同方面与FOXO、mTOR和Wnt/β-catenin的特定信号通路联系起来。由趋同的细胞外信号触发的持续Akt激活可激活一个转录程序，该程序可增强效应器功能，驱动末端效应器的分化，并降低ctl存活和分化为记忆细胞的潜力。虽然Akt的持续激活严重损害了CD8 T细胞的记忆和保护性免疫，但在体内抑制Akt可使slec免于缺失，并增加记忆性CD8 T细胞的数量。因此，来自信号分子（如TCR、共刺激分子和细胞因子受体）的趋同信号的累积强度决定了Akt激活的幅度，进而控制了长寿记忆细胞的产生。这些发现表明，治疗性调节Akt可能是增强疫苗诱导免疫的一种策略。
During a T cell response, the effector CTL pool contains two cellular subsets: short-lived effector cells (SLECs), a majority of which are destined for apoptosis, and the memory precursor effector cells (MPECs) that differentiate into memory cells. Understanding the mechanisms that govern the differentiation of memory CD8 T cells is of fundamental importance in the development of effective CD8 T cell-based vaccines. The strength and nature of TCR signaling along with signals delivered by cytokines like IL-2 and IL-12influence differentiation of SLECs and MPECs. A central question is, how are signals emanating from multiple receptors integrated and interpreted to define the fate of effector CTLs? Using genetic and pharmacological tools, we have identified Akt as a signal integrator that links distinct facets of CTL differentiation to the specific signaling pathways of FOXO, mTOR, and Wnt/β-catenin. Sustained Akt activation triggered by convergent extracellular signals evokes a transcription program that enhances effector functions, drives differentiation of terminal effectors, and diminishes the CTLs’ potential to survive and differentiate into memory cells. While sustained Akt activation severely impaired CD8 T cell memory and protective immunity, in vivo inhibition of Akt rescued SLECs from deletion and increased the number of memory CD8 T cells. Thus, the cumulative strength of convergent signals from signaling molecules such as TCR, costimulatory molecules, and cytokine receptors governs the magnitude of Akt activation, which in turn controls the generation of long-lived memory cells. These findings suggest that therapeutic modulation of Akt might be a strategy to augment vaccine-induced immunity.
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蛋白激酶B控制着指导细胞毒性T细胞命运但对于T细胞代谢的转录程序。
影响因子：
32.4
作者：
Macintyre AN;Finlay D;Preston G;Sinclair LV;Waugh CM;Tamas P;Feijoo C;Okkenhaug K;Cantrell DA
通讯作者：
Cantrell DA
DOI：
10.1038/nri2888
发表时间：
2011-02
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
30.5
作者：
Kaech, SM;Tan, JT;Ahmed, R
通讯作者：
Ahmed, R
影响因子：
30.5
作者：
Intlekofer, AM;Takemoto, N;Reiner, SL
通讯作者：
Reiner, SL