Growing evidence suggests that conventional dendritic cells (cDCs) undergo aberrant maturation in COVID-19, which negatively affects T-cell activation. The presence of effector T cells in patients with mild disease and dysfunctional T cells in severely ill patients suggests that adequate T-cell responses limit disease severity. Understanding how cDCs cope with SARS-CoV-2 can help elucidate how protective immune responses are generated. Here, we report that cDC2 subtypes exhibit similar infection-induced gene signatures, with the upregulation of IFN-stimulated genes and IL-6 signaling pathways. Furthermore, comparison of cDCs between patients with severe and mild disease showed severely ill patients to exhibit profound downregulation of genes encoding molecules involved in antigen presentation, such as MHCII, TAP, and costimulatory proteins, whereas we observed the opposite for proinflammatory molecules, such as complement and coagulation factors. Thus, as disease severity increases, cDC2s exhibit enhanced inflammatory properties and lose antigen presentation capacity. Moreover, DC3s showed upregulation of anti-apoptotic genes and accumulated during infection. Direct exposure of cDC2s to the virus in vitro recapitulated the activation profile observed in vivo. Our findings suggest that SARS-CoV-2 interacts directly with cDC2s and implements an efficient immune escape mechanism that correlates with disease severity by downregulating crucial molecules required for T-cell activation.

中文翻译：

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COVID-19 中常规树突状细胞亚型的成熟特征表明直接病毒感应

越来越多的证据表明，常规树突状细胞 (cDC) 在 COVID-19 中经历了异常成熟，这对 T 细胞活化产生了负面影响。轻度疾病患者中存在效应 T 细胞，重症患者中存在功能失调的 T 细胞表明足够的 T 细胞反应限制了疾病的严重程度。了解 cDC 如何应对 SARS-CoV-2 有助于阐明保护性免疫反应是如何产生的。在这里，我们报告 cDC2 亚型表现出相似的感染诱导基因特征，上调 IFN 刺激的基因和 IL-6 信号通路。此外，重症和轻度疾病患者之间的 cDC 比较显示重症患者表现出编码参与抗原呈递的分子的基因的显着下调，例如 MHCII、TAP 和共刺激蛋白，而我们观察到促炎分子相反，例如补体和凝血因子。因此，随着疾病严重程度的增加，cDC2 表现出增强的炎症特性并失去抗原呈递能力。此外，DC3s 表现出抗凋亡基因的上调，并在感染过程中积累。在体外将 cDC2s 直接暴露于病毒中概括了在体内观察到的激活曲线。我们的研究结果表明，SARS-CoV-2 直接与 cDC2 相互作用，并通过下调 T 细胞活化所需的关键分子实现与疾病严重程度相关的有效免疫逃逸机制。cDC2s 表现出增强的炎症特性并失去抗原呈递能力。此外，DC3s 表现出抗凋亡基因的上调，并在感染过程中积累。在体外将 cDC2s 直接暴露于病毒中概括了在体内观察到的激活曲线。我们的研究结果表明，SARS-CoV-2 直接与 cDC2 相互作用，并通过下调 T 细胞活化所需的关键分子实现与疾病严重程度相关的有效免疫逃逸机制。cDC2s 表现出增强的炎症特性并失去抗原呈递能力。此外，DC3s 表现出抗凋亡基因的上调，并在感染过程中积累。在体外将 cDC2s 直接暴露于病毒中概括了在体内观察到的激活曲线。我们的研究结果表明，SARS-CoV-2 直接与 cDC2 相互作用，并通过下调 T 细胞活化所需的关键分子实现与疾病严重程度相关的有效免疫逃逸机制。