The Chemokine CCL5 Regulates Glucose Uptake and AMP Kinase Signaling in Activated T Cells to Facilitate Chemotaxis
The Chemokine CCL5 Regulates Glucose Uptake and AMP Kinase Signaling in Activated T Cells to Facilitate Chemotaxis
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DOI：
10.1074/jbc.m112.348946
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发表时间：
2012-08-24
影响因子：
4.8
通讯作者：
Fish, Eleanor N.
中科院分区：
文献类型：
--
作者：
Chan, Olivia;Burke, J. Daniel;Fish, Eleanor N.
将效应T细胞募集到感染或炎症部位对于有效的适应性免疫应答至关重要。趋化因子CCL 5（RANTES）激活其同源受体CCR 5以启动细胞功能，包括趋化性。在早期的研究中，我们报道了CCL 5诱导的CCR 5信号激活mTOR/4 E-BP 1通路，直接调节mRNA翻译。具体而言，CCL 5介导的mTOR激活通过启动趋化性相关蛋白的合成而有助于T细胞趋化性。趋化性相关蛋白的上调可以使T细胞进行有效的迁移。现在很清楚，mTOR也是营养感测和糖酵解的中心调节因子。在此，我们描述了CCL 5介导的葡萄糖摄取和ATP积累的作用，以满足活化T细胞趋化性的能量需求。我们提供了CCL 5能够以mTOR依赖性方式诱导葡萄糖摄取的证据。CCL 5处理离体活化的人CD 3（+）T细胞也诱导营养敏感激酶AMPK和下游底物ACC-1、PFKFB-2和GSK-3 β的活化。使用2-脱氧-D-葡萄糖（葡萄糖摄取的抑制剂）和化合物C（AMPK的抑制剂），提供了实验数据，其证明CCL 5介导的T细胞趋化性依赖于葡萄糖，因为这些抑制剂以剂量依赖性方式抑制CCL 5介导的趋化性。总之，这些发现表明糖酵解和AMPK信号传导是响应于CCL 5的有效T细胞迁移所必需的。这些研究将CCL 5介导的CCR 5信号传导的作用扩展到淋巴细胞趋化性之外，并证明趋化因子在促进葡萄糖摄取和ATP产生以匹配迁移的能量需求中的作用。
Recruitment of effector T cells to sites of infection or inflammation is essential for an effective adaptive immune response. The chemokine CCL5 (RANTES) activates its cognate receptor, CCR5, to initiate cellular functions, including chemotaxis. In earlier studies, we reported that CCL5-induced CCR5 signaling activates the mTOR/4E-BP1 pathway to directly modulate mRNA translation. Specifically, CCL5-mediated mTOR activation contributes to T cell chemotaxis by initiating the synthesis of chemotaxis-related proteins. Up-regulation of chemotaxis-related proteins may prime T cells for efficient migration. It is now clear that mTOR is also a central regulator of nutrient sensing and glycolysis. Herein we describe a role for CCL5-mediated glucose uptake and ATP accumulation to meet the energy demands of chemotaxis in activated T cells. We provide evidence that CCL5 is able to induce glucose uptake in an mTOR-dependent manner. CCL5 treatment of ex vivo activated human CD3(+) T cells also induced the activation of the nutrient-sensing kinase AMPK and downstream substrates ACC-1, PFKFB-2, and GSK-3 beta. Using 2-deoxy-D-glucose, an inhibitor of glucose uptake, and compound C, an inhibitor of AMPK, experimental data are presented that demonstrate that CCL5-mediated T cell chemotaxis is dependent on glucose, as these inhibitors inhibit CCL5-mediated chemotaxis in a dose-dependent manner. Altogether, these findings suggest that both glycolysis and AMPK signaling are required for efficient T cell migration in response to CCL5. These studies extend the role of CCL5 mediated CCR5 signaling beyond lymphocyte chemotaxis and demonstrate a role for chemokines in promoting glucose uptake and ATP production to match energy demands of migration.