The liver kinase B1 is a central regulator of T cell development, activation, and metabolism.
The liver kinase B1 is a central regulator of T cell development, activation, and metabolism.
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DOI：
10.4049/jimmunol.1100367
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发表时间：
2011-10-15
期刊：
影响因子：
--
通讯作者：
Jones RG
中科院分区：
文献类型：
--
作者：
MacIver NJ;Blagih J;Saucillo DC;Tonelli L;Griss T;Rathmell JC;Jones RG
T细胞活化导致支持细胞增殖和功能所必需的细胞代谢途径的参与。然而，我们对调节代谢的信号转导途径及其对T细胞功能的影响的理解仍然有限。肝激酶B1（LKB 1）是一种丝氨酸/苏氨酸激酶，将细胞代谢与细胞生长和增殖联系起来。在这里，我们证明了LKB 1是T细胞发育，活力，活化和代谢的关键调节因子。T细胞特异性切除编码LKB 1的基因导致胸腺细胞发育受阻和外周T细胞减少。LKB 1缺陷型T细胞表现出细胞增殖和活力的缺陷，并改变了糖酵解和脂质代谢。有趣的是，LKB 1的缺失促进了T细胞活化和CD 4+和CD 8 + T细胞的炎性细胞因子产生。AMP活化蛋白激酶（AMPK）的活化在LKB 1缺陷型T细胞中减少。AMPK被发现在T淋巴细胞中介导LKB 1功能的一个子集，因为缺乏AMPK α1亚基的小鼠在T细胞活化、代谢和炎性细胞因子产生方面表现出类似的缺陷，但正常的T细胞发育和外周T细胞稳态。LKB 1和AMPKα1缺陷型T细胞均显示mTORC 1信号传导和IFN-γ产生升高，雷帕霉素处理可逆转这一现象。我们的数据突出了LKB 1在T细胞活化、活力和代谢中的核心作用，并表明LKB 1-AMPK信号通过调节mTOR活性来负调节T细胞效应器功能。
T cell activation leads to engagement of cellular metabolic pathways necessary to support cell proliferation and function. However, our understanding of the signal transduction pathways that regulate metabolism and their impact on T cell function remains limited. The Liver Kinase B1 (LKB1) is a serine/threonine kinase that links cellular metabolism with cell growth and proliferation. Here we demonstrate that LKB1 is a critical regulator of T cell development, viability, activation, and metabolism. T cell-specific ablation of the gene that encodes LKB1 resulted in blocked thymocyte development and a reduction in peripheral T cells. LKB1-deficient T cells exhibited defects in cell proliferation and viability, and altered glycolytic and lipid metabolism. Interestingly, loss of LKB1 promoted increased T cell activation and inflammatory cytokine production by both CD4+ and CD8+ T cells. Activation of the AMP-activated protein kinase (AMPK) was decreased in LKB1-deficient T cells. AMPK was found to mediate a subset of LKB1 functions in T lymphocytes, as mice lacking the α1 subunit of AMPK displayed similar defects in T cell activation, metabolism, and inflammatory cytokine production, but normal T cell development and peripheral T cell homeostasis. LKB1- and AMPKα1-deficient T cells each displayed elevated mTORC1 signaling and IFN-γ production that could be reversed by rapamycin treatment. Our data highlight a central role for LKB1 in T cell activation, viability, and metabolism, and suggest that LKB1-AMPK signaling negatively regulates T cell effector function through regulation of mTOR activity.
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影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
DOI：
10.4049/jimmunol.0902593
发表时间：
2010-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Jacobs SR;Michalek RD;Rathmell JC
通讯作者：
Rathmell JC
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：
32.4
作者：
Jones, Russell G.;Bui, Thi;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
影响因子：
3.3
作者：
BENTAL, M;DEUTSCH, C
通讯作者：
DEUTSCH, C