Proteomic analysis in primary T cells reveals IL-7 alters T cell receptor thresholding via CYTIP/cytohesin/LFA-1 localisation and activation.
Proteomic analysis in primary T cells reveals IL-7 alters T cell receptor thresholding via CYTIP/cytohesin/LFA-1 localisation and activation.
复制标题
原代T细胞的蛋白质组学分析显示，IL-7通过CYTIP/cytohesin/LFA-1的定位和激活改变T细胞受体阈值。
DOI：
10.1042/bcj20210313
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发表时间：
2022-02-11
期刊：
影响因子：
--
通讯作者：
Finch DK
中科院分区：
文献类型：
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作者：
Queiroz RML;Piper SC;Rees JS;Strickson S;Briend E;Low CP;Ferguson GJ;Lilley KS;Jackson AP;Finch DK
细胞免疫系统区分自身抗原和外来抗原的能力取决于T细胞受体（TCR）信号阈值的适当校准。已知淋巴细胞稳态细胞因子白细胞介素7 （IL-7）影响TCR阈值，但分子机制尚未完全阐明。更好地了解这一过程在自身免疫性疾病治疗和癌症免疫治疗的背景下是高度相关的。我们试图描述可归因于IL-7启动的早期信号事件；特别是，信号转导蛋白磷酸化的改变及其对TCR的分子定位。通过整合高分辨率接近磷酸化蛋白质组学和成像方法，使用原代T细胞，而不是工程细胞系或体外扩增的T细胞群，我们发现了以前与IL-7无关的转导事件。研究人员发现，IL-7可导致迄今为止未描述的磷酸化位点（pThr280）上的细胞增殖素相互作用蛋白（CYTIP）去磷酸化，并改变细胞增殖素-1与TCR和LFA-1整合素的共定位。这些结果表明，IL-7通过CYTIP和cytohesin-1起作用，可能通过增强TCR和LFA-1整合素的共聚而影响TCR的激活阈值。
The ability of the cellular immune system to discriminate self from foreign antigens depends on the appropriate calibration of the T cell receptor (TCR) signalling threshold. The lymphocyte homeostatic cytokine interleukin 7 (IL-7) is known to affect TCR thresholding, but the molecular mechanism is not fully elucidated. A better understanding of this process is highly relevant in the context of autoimmune disease therapy and cancer immunotherapy. We sought to characterise the early signalling events attributable to IL-7 priming; in particular, the altered phosphorylation of signal transduction proteins and their molecular localisation to the TCR. By integrating high-resolution proximity- phospho-proteomic and imaging approaches using primary T cells, rather than engineered cell lines or an in vitro expanded T cell population, we uncovered transduction events previously not linked to IL-7. We show that IL-7 leads to dephosphorylation of cytohesin interacting protein (CYTIP) at a hitherto undescribed phosphorylation site (pThr280) and alters the co-localisation of cytohesin-1 with the TCR and LFA-1 integrin. These results show that IL-7, acting via CYTIP and cytohesin-1, may impact TCR activation thresholds by enhancing the co-clustering of TCR and LFA-1 integrin.