Defining the cytotoxic T cell response in COVID-19 patients

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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.