Galectin-3 negatively regulates TCR-mediated CD4+ T-cell activation at the immunological synapse
Galectin-3 negatively regulates TCR-mediated CD4+ T-cell activation at the immunological synapse
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DOI：
10.1073/pnas.0903497106
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发表时间：
2009-08-25
影响因子：
11.1
通讯作者：
Liu, Fu-Tong
中科院分区：
文献类型：
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作者：
Chen, Huan-Yuan;Fermin, Agnes;Liu, Fu-Tong
我们研究了内源性半乳糖凝集素-3在T细胞中的功能。在T细胞受体（TCR）作用后，gal3(-/-) CD4(+) T细胞比gal3(+/+) CD4(+) T细胞分泌更多的ifn - γ和IL-4。在活化的T细胞中，半乳糖凝集素-3被募集到免疫突触（IS）的细胞质侧。在支持脂质双分子层刺激的T细胞中，半乳糖凝集素-3主要位于外周超分子激活簇（pSMAC）。与Gal3(-/-) T细胞相比，Gal3(+/+) T细胞在脂质双层上形成中央SMAC的效率较低，并且与抗原呈递细胞的粘附程度较低，这表明半乳糖凝集素-3破坏了IS的稳定性。半乳糖凝集素-3的表达与pSMAC的早期信号事件和磷酸酪氨酸信号水平较低有关。其他数据表明半乳糖凝集素-3增强了T细胞中TCR的下调。通过酵母双杂交筛选，我们确定了半乳糖凝集素-3结合伙伴Alix，已知它参与蛋白质运输和某些受体细胞表面表达的调节。免疫共沉淀证实了半凝集素-3-Alix的关联，免疫荧光分析证实了激活T细胞中Alix向IS的易位。我们得出结论，半乳糖凝集素-3是t细胞活化的抑制调节剂，并通过促进TCR下调在细胞内发挥作用，可能通过调节Alix在is的功能。
We have investigated the function of endogenous galectin-3 in T cells. Galectin-3-deficient (gal3(-/-)) CD4(+) T cells secreted more IFN-gamma and IL-4 than gal3(+/+) CD4(+) T cells after T-cell receptor (TCR) engagement. Galectin-3 was recruited to the cytoplasmic side of the immunological synapse (IS) in activated T cells. In T cells stimulated on supported lipid bilayers, galectin-3 was primarily located at the peripheral supramolecular activation cluster (pSMAC). Gal3(+/+) T cells formed central SMAC on lipid bilayers less effectively and adhered to antigen-presenting cells less firmly than gal3(-/-) T cells, suggesting that galectin-3 destabilizes the IS. Galectin-3 expression was associated with lower levels of early signaling events and phosphotyrosine signals at the pSMAC. Additional data suggest that galectin-3 potentiates down-regulation of TCR in T cells. By yeast two-hybrid screening, we identified as a galectin-3-binding partner, Alix, which is known to be involved in protein transport and regulation of cell surface expression of certain receptors. Co-immunoprecipitation confirmed galectin-3-Alix association and immunofluorescence analysis demonstrated the translocation of Alix to the IS in activated T cells. We conclude that galectin-3 is an inhibitory regulator of T-cell activation and functions intracellularly by promoting TCR down-regulation, possibly through modulating Alix's function at the IS.