Abstract
Hyperinflammation contributes to lung injury and subsequent acute respiratory distress syndrome (ARDS) with high mortality in patients with severe coronavirus disease 2019 (COVID-19). To understand the underlying mechanisms involved in lung pathology, we investigated the role of the lung-specific immune response. We profiled immune cells in bronchoalveolar lavage fluid and blood collected from COVID-19 patients with severe disease and bacterial pneumonia patients not associated with viral infection. By tracking T cell clones across tissues, we identified clonally expanded tissue-resident memory-like Th17 cells (Trm17 cells) in the lungs even after viral clearance. These Trm17 cells were characterized by a a potentially pathogenic cytokine expression profile of IL17A and CSF2 (GM-CSF). Interactome analysis suggests that Trm17 cells can interact with lung 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 were associated with a more severe clinical course. Collectively, our study suggests that pulmonary Trm17 cells are one potential orchestrator of the hyperinflammation in severe COVID-19.
Highlights
On 11 March 2020, the World Health Organization (WHO) communicated that the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had reached pandemic status
All samples were analyzed by flow cytometry and T cells were fluorescence-activated cell sorting (FACS)–sorted and subjected to scRNA and T cell receptor (TCR) sequencing, as well as to sequencing-based epitope measurement [cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq)]
Clonal expansion does not necessarily reflect Ag specificity; we investigated whether SARS-CoV-2– specific T cell clones are present in the BAL fluid (BALF) by comparing the TCRs identified in our study with those of two publicly available datasets of SARS-CoV-2–specific TCR sequences obtained from peripheral blood [25, 26]
Summary
On 11 March 2020, the World Health Organization (WHO) communicated that the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had reached pandemic status. By the end of 2020, there were more than 80 million confirmed cases including 1.7 million deaths [1]. These epidemiological data highlight the need to rapidly develop therapies for treating COVID-19 that reduce the high case fatality rate. The promising results of the clinical trial RECOVERY, in which dexamethasone was administered to 2104 patients with COVID-19 [2], suggest that one of the causes of the acute respiratory distress syndrome and death of patients with COVID-19 is the hyperactivation of the immune system. Supporting the pathogenic role of immune hyperactivation, the use of neutralizing antibodies, blocking, for example, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-1 (IL-1 ), has shown encouraging clinical results [3,4,5,6]. The efficacy of a therapy blocking IL-6 has not yet been broadly recognized [7], but one recent study showed that tocilizumab reduced disease progression in patients with COVID-19 not receiving mechanical ventilation [8]
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