Stromal cell-derived factor-1 signaling via the CXCR4-TCR heterodimer requires phospholipase C-β3 and phospholipase C-γ1 for distinct cellular responses.
Stromal cell-derived factor-1 signaling via the CXCR4-TCR heterodimer requires phospholipase C-β3 and phospholipase C-γ1 for distinct cellular responses.
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DOI：
10.4049/jimmunol.1100820
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发表时间：
2011-08-01
期刊：
影响因子：
--
通讯作者：
Hedin KE
中科院分区：
文献类型：
--
作者：
Kremer KN;Clift IC;Miamen AG;Bamidele AO;Qian NX;Humphreys TD;Hedin KE
CXCR4趋化因子受体是一种G蛋白偶联受体（GPCR），通过与T细胞抗原受体（TCR）形成异源二聚体在T淋巴细胞中发出信号。因此，CXCR4和TCR功能高度交叉调节，影响T细胞免疫激活、细胞因子分泌和T细胞迁移。CXCR4- tcr异源二聚体刺激T细胞迁移，激活ERK MAP激酶和下游ap -1依赖性细胞因子转录，以响应SDF-1 （CXCR4唯一的趋化因子配体）。这些反应需要gi型G蛋白以及TCR ITAM结构域和ZAP-70酪氨酸激酶，从而表明CXCR4-TCR异源二聚体信号整合gpcr相关和TCR相关信号分子以响应SDF-1。然而，负责将CXCR4-TCR异源二聚体偶联到不同下游细胞反应的磷脂酶C （PLC）同工酶尚未完全表征。在这里，我们证明了在人T细胞中，SDF-1诱导ERK激活、迁移和CXCR4内吞是需要PLC活性的。通过CXCR4-TCR异源二聚体的SDF-1信号通路使用PLC-β3激活Ras-ERK通路并增加细胞内Ca2+浓度，而PLC-γ1对于这些结果是必不可少的。相反，sdf -1介导的迁移需要PLC-γ -1，而不需要PLC-β3，其机制独立于LAT。这些结果增加了对CXCR4-TCR异源二聚体所使用的信号机制的理解，表征了PLC-β3和PLC-γ1在T细胞中的新作用，并表明多个PLC也可能在其他趋化因子受体的下游被激活，从而明显调节迁移与其他信号功能。
The CXCR4 chemokine receptor is a G protein-coupled receptor (GPCR) that signals in T lymphocytes by forming a heterodimer with the T cell antigen receptor (TCR). CXCR4 and TCR functions are consequently highly cross-regulated, affecting T cell immune activation, cytokine secretion, and T cell migration. The CXCR4-TCR heterodimer stimulates T cell migration and activation of the ERK MAP kinase and downstream AP-1-dependent cytokine transcription in response to SDF-1, the sole chemokine ligand of CXCR4. These responses require Gi-type G proteins as well as TCR ITAM domains and the ZAP-70 tyrosine kinase, thus indicating that the CXCR4-TCR heterodimer signals to integrate GPCR-associated and TCR-associated signaling molecules in response to SDF-1. Yet, the phospholipase C (PLC) isozymes responsible for coupling the CXCR4-TCR heterodimer to distinct downstream cellular responses are incompletely characterized. Here, we demonstrate that PLC activity is required for SDF-1 to induce ERK activation, migration, and CXCR4 endocytosis in human T cells. SDF-1 signaling via the CXCR4-TCR heterodimer uses PLC-β3 to activate the Ras-ERK pathway and increase intracellular Ca2+ concentrations, while PLC-γ1 is dispensable for these outcomes. In contrast, PLC-γ1, but not PLC-β3, is required for SDF-1-mediated migration, via a mechanism independent of LAT. These results increase understanding of the signaling mechanisms employed by the CXCR4-TCR heterodimer, characterize new roles for PLC-β3 and PLC-γ1 in T cells, and suggest that multiple PLCs may also be activated downstream of other chemokine receptors in order to distinctly regulate migration versus other signaling functions.
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