Syntaxin 8是细胞毒性T淋巴细胞有效裂解颗粒运输所必需的。,Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Syntaxin 8是细胞毒性T淋巴细胞有效裂解颗粒运输所必需的。
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ( IF 4.6 ) Pub Date : 2016-04-21 , DOI: 10.1016/j.bbamcr.2016.04.014
Shruthi S Bhat ₁ , Kim S Friedmann ₁ , Arne Knörck ₁ , Cora Hoxha ₁ , Petra Leidinger ₂ , Christina Backes ₃ , Eckart Meese ₂ , Andreas Keller ₃ , Jens Rettig ₄ , Markus Hoth ₁ , Bin Qu ₁ , Eva C Schwarz ₁

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细胞毒性T淋巴细胞（CTL）主要通过在免疫突触（IS）上极化分泌溶胞颗粒（LG，含有诸如穿孔素和颗粒酶等细胞毒性分子）来极化分泌物，从而消除病原体感染和癌细胞。SNARE（可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体）家族的成员参与IS处囊泡的运输（生成，运输和融合）。Syntaxin 8（Stx8）在LG中表达，并在IS形成后与T细胞受体（TCR）共定位。在这里，我们报告Stx8对人类CTL细胞毒性的意义。我们发现Stx8主要位于晚期，回收的内体和溶酶体区室，早期内体区室很少表达。siRNA对Stx8的下调导致细胞毒性降低。我们发现，在靶细胞接触后，穿孔素释放预先存在的池，与对照CTL相比，Stx8下调的CTL再生穿孔素池的效率较低，因此释放的穿孔素更少。CD107a脱颗粒，实时和终点人群细胞毒性测定以及高分辨率显微镜技术支持我们的结论，即Stx8是通过人CTL的内体途径正确，及时地将细胞毒性分子正确分类和运输至功能LG所必需的。

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Syntaxin 8 is required for efficient lytic granule trafficking in cytotoxic T lymphocytes.

Cytotoxic T lymphocytes (CTL) eliminate pathogen-infected and cancerous cells mainly by polarized secretion of lytic granules (LG, containing cytotoxic molecules like perforin and granzymes) at the immunological synapse (IS). Members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) family are involved in trafficking (generation, transport and fusion) of vesicles at the IS. Syntaxin 8 (Stx8) is expressed in LG and colocalizes with the T cell receptor (TCR) upon IS formation. Here, we report the significance of Stx8 for human CTL cytotoxicity. We found that Stx8 mostly localized in late, recycling endosomal and lysosomal compartments with little expression in early endosomal compartments. Down-regulation of Stx8 by siRNA resulted in reduced cytotoxicity. We found that following perforin release of the pre-existing pool upon target cell contact, Stx8 down-regulated CTL regenerate perforin pools less efficiently and thus release less perforin compared to control CTL. CD107a degranulation, real-time and end-point population cytotoxicity assays, and high resolution microscopy support our conclusion that Stx8 is required for proper and timely sorting and trafficking of cytotoxic molecules to functional LG through the endosomal pathway in human CTL.

更新日期：2019-11-01

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