Defining the cytotoxic T cell response in COVID-19 patients

细胞毒性T细胞负责消除受感染的细胞，是控制病毒的关键参与者。CD 8 + T细胞、CD 4 + T细胞和NK细胞是主要的细胞毒性细胞群，它们能够执行靶细胞杀伤。免疫效应分子的颗粒酶（Gzm）家族是在细胞毒性T细胞或NK细胞的分泌颗粒中检测到的丝氨酸蛋白酶。Gzms能够诱导特定的促炎和抗病毒作用。细胞毒性细胞群被诱导以响应SARS-CoV-2。然而，关于这些细胞在COVID-19期间的作用的观点仍然相互矛盾。一些研究显示，T细胞功能增强与穿孔素和Gzms表达增加以及COVID-19患者T细胞和NK细胞中促炎细胞因子产生增加相关。其他研究观察到表达抑制性分子的功能失调或“耗尽”T细胞，并显示对再刺激的反应降低（9，10）。主要问题：在感染过程中，不同（多功能）细胞类型（CD 8 T细胞和NK细胞）产生哪些特定的Gzms，Gzms的表达与穿孔素的产生如何相关？哪些Gzms优先有助于SARS-CoV-2感染靶细胞的细胞溶解消除？哪些细胞类型分泌Gzms并导致器官炎症。血液和肺中T和NK细胞的细胞毒性特征是什么？在体外SARS-CoV-2感染靶细胞后，细胞毒性T细胞上表达哪些抑制性受体，哪些抑制性配体上调？Gzms能在体外感染的靶细胞中切割细胞或病毒蛋白吗？通过我们的研究，我们的目标是更好地确定特异性Gzms和穿孔素在控制SARS-CoV-2和诱导肺炎中的抗病毒作用，并为COVID-19的未来免疫调节治疗确定新的靶点。

Cytotoxic T cells are responsible for the elimination of infected cells and are key players for the control of viruses. CD8+ T cells, CD4+ T cells and NK cells are the main cytotoxic populations, which able to perform target cell killing. The granzyme (Gzm) family of immunological effector molecules are serine proteases that are detected in secretory granula of cytotoxic T cells or NK cells. Gzms are able to induce specific pro-inflammatory and antiviral effects. A population of cytotoxic cells is induced in response to SARS-CoV-2. However, views on the role of these cells during COVID-19 remain contradictory. Some studies show an enhanced T cell functionality associated with increasing expression of perforin and Gzms and an enhanced production of proinflammatory cytokines in T cells and NK cells of COVID-19 patients. Other studies observed dysfunctional or “exhausted” T cells that express inhibitory molecules and show a reduced response to re-stimulation (9, 10). Main questions: Which specific Gzms are produced by different (multifunctional) cell types (CD8 T cell and NK cells) during infection and how does the expression of Gzms correlate with the production of perforin? Which Gzms preferentially contribute to the cytolytic elimination of SARS-CoV-2 infected target cells? Which cell types secrete Gzms and contribute to organ inflammation. What is the cytotoxic profile of T and NK cells in the blood versus the lung? Which inhibitory receptors are expressed on cytotoxic T cells and which inhibitory ligands are upregulated after in vitro SARS-CoV-2 infection on target cells? Can Gzms cleave cellular or viral proteins in in vitro infected target cells? With our study we aim to better define the anti-viral role of specific Gzms and perforin in the control of SARS-CoV-2 and the induction of pneumonia and define new targets for future immunomodulating therapies of COVID-19.