Clonal expansion and activation of tissue-resident memory-like Th17 cells expressing GM-CSF in the lung of severe COVID-19 patients

Hyperinflammation contributes to lung injury and subsequent acute respiratory distress syndrome (ARDS) with high mortality in severe COVID-19. To understand the underlying mechanisms, we investigated the role of the lung-specific immune response. Here we profiled lymphocytes and myeloid cells in the bronchoalveolar lavage (BAL) fluid and blood of COVID-19 patients. By tracking T cell clones across tissues, we identified clonally expanded tissue-resident memory-like Th17 cells (Trm17 cells) in the lung even after viral clearance. These Trm17 cells are characterized by a potentially pathogenic cytokine profile with expression of IL17A and CSF2 (GM-CSF). Interactome analysis revealed that Trm17 cells interact with macrophages and cytotoxic CD8+ T cells, which have been associated with disease severity and lung damage. High IL-17A and GM-CSF protein levels in the serum of COVID-19 patients correlated with severe clinical course. This study suggests pulmonary Trm17 cells as one of the orchestrators of the hyperinflammation in severe COVID-19 and that these cells and their cytokines, such as GM-CSF, are promising biomarkers and potential targets for a COVID-19 therapy.