Temporal profiling of CD4 T-cell activation and differentiation upon SARS-CoV-2 spike protein immunisation
Temporal profiling of CD4 T-cell activation and differentiation upon SARS-CoV-2 spike protein immunisation
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DOI：
10.1101/2022.07.21.500987
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发表时间：
2022-07
期刊：
影响因子：
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通讯作者：
José Almeida-Santos;Rita Berkachy;C. A. Tye;J. Hassan;B. Kalfaoglu;M. Selkirk;M. Ono
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文献类型：
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作者：
José Almeida-Santos;Rita Berkachy;C. A. Tye;J. Hassan;B. Kalfaoglu;M. Selkirk;M. Ono
CD4 T细胞需要T细胞受体（TCR）信号传导用于其活化和分化。Foxp3+调节性T细胞（Treg）的分化和抑制功能依赖于TCR信号。然而，还不完全知道TCR信号传导如何在体内单细胞水平上在抗原识别时控制多克隆CD4 T细胞的分化。在这项研究中，使用Nr4a3-Tocky（细胞动力学和活性计时器），分析TCR信号传导后抗原反应性T细胞的时间变化，我们研究了免疫后T细胞对刺突蛋白片段（S1a，S1b，S2a和S2b）的反应。我们发现S1a和S2a诱导PD1hiCXCR5 + T滤泡辅助细胞（Tfh）分化，这与CD4 T细胞免疫原性有关。相反，S1b诱导CD25hiGITRhiPD-1int Treg，其间歇性地接收TCR信号。使用Foxp3-Tocky分析Foxp3转录动力学，S1b反应性Treg随着时间的推移维持Foxp3转录，这是活化Treg的标志。Foxp3基因定位显示，S1b反应性Treg不是来自预先存在的胸腺Treg，表明Foxp3在非Treg细胞中诱导。因此，本研究揭示了在多克隆TCR库中免疫后CD4 T细胞和Treg的时间动态分化。
CD4 T-cells require T-cell receptor (TCR) signalling for their activation and differentiation. Foxp3+ regulatory T-cells (Treg) are dependent on TCR signals for their differentiation and suppressive function. However, it is not fully known how TCR signalling controls the differentiation of polyclonal CD4 T-cells upon antigen recognition at the single-cell level in vivo. In this study, using Nr4a3-Tocky (Timer-of-cell-kinetics-and-activity), which analyses temporal changes of antigen-reactive T-cells following TCR signalling, we investigated T-cell response to Spike protein fragments (S1a, S1b, S2a, and S2b) upon immunisation. We show that S1a and S2a induced the differentiation of PD1hiCXCR5+ T follicular helper (Tfh) cells, which is related to CD4 T-cell immunogenicity. In contrast, S1b induced CD25hiGITRhiPD-1int Treg, which intermittently received TCR signalling. Using Foxp3-Tocky, which analyses Foxp3 transcriptional dynamics, the S1b-reactive Treg sustained Foxp3 transcription over time, which is a hallmark of activated Treg. Foxp3 fate-mapping showed that the S1b-reactive Treg were derived not from pre-existing thymic Treg, suggesting Foxp3 induction in non-Treg cells. Thus, the current study reveals temporally dynamic differentiation of CD4 T-cells and Treg upon immunisation in the polyclonal TCR repertoire.