Generation of glucocorticoid-resistant SARS-CoV-2 T cells for adoptive cell therapy.
Generation of glucocorticoid-resistant SARS-CoV-2 T cells for adoptive cell therapy.
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DOI：
10.1016/j.celrep.2021.109432
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发表时间：
2021-07-20
期刊：
影响因子：
8.8
通讯作者：
Rezvani K
中科院分区：
文献类型：
--
作者：
Basar R;Uprety N;Ensley E;Daher M;Klein K;Martinez F;Aung F;Shanley M;Hu B;Gokdemir E;Nunez Cortes AK;Mendt M;Reyes Silva F;Acharya S;Laskowski T;Muniz-Feliciano L;Banerjee PP;Li Y;Li S;Melo Garcia L;Lin P;Shaim H;Yates SG;Marin D;Kaur I;Rao S;Mak D;Lin A;Miao Q;Dou J;Chen K;Champlin RE;Shpall EJ;Rezvani K
使用病毒特异性T细胞的免疫细胞疗法已成功用于治疗危及生命的病毒感染，支持将这种方法应用于2019冠状病毒病（COVID-19）。我们使用不同的培养条件从COVID-19康复供体和未暴露对照的外周血中扩增了严重急性呼吸综合征冠状病毒2（SARS-CoV-2）T细胞。我们观察到细胞因子的选择调节SARS-CoV-2 T细胞的抗原识别的扩增、表型和层次。与基线（扩增前）样品相比，用白细胞介素（IL）-2/4/7培养，而不是在其他干扰素驱动的条件下培养，导致SARS-CoV-2 T细胞扩增超过1,000倍，保留了抗原识别的表型、功能和层次。扩增的细胞毒性T淋巴细胞（CTL）针对结构SARS-CoV-2蛋白，包括Spike的受体结合结构域。SARS-CoV-2 T细胞不能从未暴露对照的外周血中有效扩增。由于皮质类固醇被用于严重COVID-19的管理，我们提出了一种有效的策略，使用CRISPR-Cas9基因编辑来修饰SARS-CoV-2 CTL中的糖皮质激素受体基因（NR 3C 1）。Basar等人证明SARS-CoV-2 T细胞可以从回收COVID 19的供体中有效产生，对多种结构SARS-CoV-2蛋白（包括刺突蛋白）具有特异性。此外，这些细胞可以进行遗传修饰，使它们对皮质类固醇具有抗性，使其临床应用可行。
Adoptive cell therapy with virus-specific T cells has been used successfully to treat life-threatening viral infections, supporting application of this approach to coronavirus disease 2019 (COVID-19). We expand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T cells from the peripheral blood of COVID-19-recovered donors and non-exposed controls using different culture conditions. We observe that the choice of cytokines modulates the expansion, phenotype, and hierarchy of antigenic recognition by SARS-CoV-2 T cells. Culture with interleukin (IL)-2/4/7, but not under other cytokine-driven conditions, results in more than 1,000-fold expansion in SARS-CoV-2 T cells with a retained phenotype, function, and hierarchy of antigenic recognition compared with baseline (pre-expansion) samples. Expanded cytotoxic T lymphocytes (CTLs) are directed against structural SARS-CoV-2 proteins, including the receptor-binding domain of Spike. SARS-CoV-2 T cells cannot be expanded efficiently from the peripheral blood of non-exposed controls. Because corticosteroids are used for management of severe COVID-19, we propose an efficient strategy to inactivate the glucocorticoid receptor gene (NR3C1) in SARS-CoV-2 CTLs using CRISPR-Cas9 gene editing. Basar et al. demonstrate that SARS-CoV-2 T cells can be efficiently generated from COVID19-recovered donors with specificity against multiple structural SARS-CoV-2 proteins, including the Spike protein. Moreover, these cells can be genetically modified to render them resistant to corticosteroids, making their application clinically feasible.
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