Hyperactive immune system contributes to COVID-19 severity, lung damage

Researchers have pinpointed a helper T cell population in the lungs of patients with severe COVID-19 that may be central to the development of hyperinflammation, lung injury, and subsequent acute respiratory distress syndrome (ARDS) during disease.

Their data support the ongoing investigation of anti-cytokine therapies that target this cell subset, called tissue-resident memory-like Th17 cells (Trm17). To date, the bulk of research on immune responses to COVID-19 has mainly focused on T cells in the blood, while the role of tissue-specific immune cells in the inflamed lung has remained unclear.

Accumulating evidence suggests that one of the causes of ARDS and, ultimately, death in COVID-19 patients is a hyperactive immune system, fueling exploration into drugs to block molecules that contribute to hyperactivation.

Now, using a combination of single-cell RNA sequencing, cell surface protein sequencing, and T cell analyses, Yu Zhao and colleagues identified a helper T cell subset in the lungs of patients with severe COVID-19 that express high levels of GM-CSF and IL-17A, molecules both implicated in heightened immune activation and inflammation.

The researchers collected samples from blood and lung fluid of patients with severe COVID-19 and patients with bacterial pneumonia. CD4+ cells and, in particular, Trm17 cells were more clonally expanded in the lungs of the virally infected group.

Levels of GM-CSF and IL-17A in the lungs positively correlated with disease severity in COVID-19 patients. As well, the researchers found Trm17 cells could potentially interact with other cells associated with COVID-19 severity and lung damage, such as lung macrophages and CD8+ killer T cells.

Based on their results, the authors postulate that Trm17 cells may become activated as part of a cytokine storm, during which they start producing inflammatory molecules like GM-CSF. In future work, Zhao et al. hope to validate their findings in a larger patient cohort.