Laboratory of Hematology and Stem Cells (LHCT), Faculty of Health Sciences, University of Brasília, Brasília, 70910-900, Brazil.
Laboratory of Molecular NeuroVirology, Faculty of Health Sciences, University of Brasília, Brasília, 70910-900, Brazil.
Sci Rep. 2024 Oct 16;14(1):24235. doi: 10.1038/s41598-024-75776-5.
In recent years, clinical studies have shown positive results of the application of Mesenchymal Stromal Cells (MSCs) in severe cases of COVID-19. However, the mechanisms of immunomodulation of IFN-γ licensed MSCs in SARS-CoV-2 infection are only partially understood. In this study, we first tested the effect of IFN-γ licensing in the MSC immunomodulatory profile. Then, we established an in vitro model of inflammation by exposing Calu-3 lung cells to SARS-CoV-2 nucleocapsid and spike (NS) antigens, and determined the toxicity of SARS-CoV-2 NS antigen and/or IFN-γ stimulation to Calu-3. The conditioned medium (iCM) generated by Calu-3 cells exposed to IFN-γ and SARS-CoV-2 NS antigens was used to stimulate T-cells, which were then co-cultured with IFN-γ-licensed MSCs. The exposure to IFN-γ and SARS-CoV-2 NS antigens compromised the viability of Calu-3 cells and induced the expression of the inflammatory mediators ICAM-1, CXCL-10, and IFN-β by these cells. Importantly, despite initially stimulating T-cell activation, IFN-γ-licensed MSCs dramatically reduced IL-6 and IL-10 levels secreted by T-cells exposed to NS antigens and iCM. Moreover, IFN-γ-licensed MSCs were able to significantly inhibit T-cell apoptosis induced by SARS-CoV-2 NS antigens. Taken together, our data show that, in addition to reducing the level of critical cytokines in COVID-19, IFN-γ-licensed MSCs protect T-cells from SARS-CoV-2 antigen-induced apoptosis. Such observations suggest that MSCs may contribute to COVID-19 management by preventing the lymphopenia and immunodeficiency observed in critical cases of the disease.
近年来，临床研究表明间充质基质细胞（MSCs）在 COVID-19 重症病例中的应用有积极效果。然而，干扰素 γ 授权的 MSCs 在 SARS-CoV-2 感染中的免疫调节机制仅部分被理解。在这项研究中，我们首先测试了干扰素 γ 授权对 MSC 免疫调节谱的影响。然后，我们通过用 SARS-CoV-2 核衣壳和刺突（NS）抗原暴露 Calu-3 肺细胞，建立了体外炎症模型，并确定了 SARS-CoV-2 NS 抗原和/或干扰素 γ 刺激对 Calu-3 的毒性。用 IFN-γ 和 SARS-CoV-2 NS 抗原暴露的 Calu-3 细胞生成的条件培养基（iCM）用于刺激 T 细胞，然后将这些 T 细胞与 IFN-γ 授权的 MSCs 共培养。IFN-γ 和 SARS-CoV-2 NS 抗原的暴露会降低 Calu-3 细胞的活力，并诱导这些细胞表达炎症介质 ICAM-1、CXCL-10 和 IFN-β。重要的是，尽管 IFN-γ 授权的 MSCs 最初刺激 T 细胞激活，但它们显著降低了暴露于 NS 抗原和 iCM 的 T 细胞分泌的 IL-6 和 IL-10 水平。此外，IFN-γ 授权的 MSCs 能够显著抑制 SARS-CoV-2 NS 抗原诱导的 T 细胞凋亡。总之，我们的数据表明，除了降低 COVID-19 中关键细胞因子的水平外，IFN-γ 授权的 MSCs 还可以保护 T 细胞免受 SARS-CoV-2 抗原诱导的凋亡。这些观察结果表明，MSCs 通过防止 COVID-19 重症病例中观察到的淋巴细胞减少和免疫缺陷，可能有助于 COVID-19 的管理。
