T Cell Contribution to COVID-19 Hyperinflammation
While the induction of robust T cell immunity is likely essential for efficient virus control, dysregulated T cell responses may cause immunopathology and contribute to disease severity in COVID-19 patients (Figure 3). This is suggested in a study by Zhou et al., which reported a significantly increased PBMC frequency of polyclonal GM-CSF+ CD4 T cells capable of prodigious ex vivo IL-6 and IFN-γ production only in critically ill COVID-19 patients (Zhou et al., 2020c). Of note, GM-CSF+ CD4 T cells have been previously implicated in inflammatory autoimmune diseases, such as multiple sclerosis or juvenile rheumatoid arthritis, and high levels of circulating GM-CSF+ CD4 T cells were found to be associated with poor outcomes in sepsis (Huang et al., 2019). Additionally, two studies observed reduced frequencies of Treg cells in severe COVID-19 cases (Chen et al., 2020c, Qin et al., 2020). Since Treg cells have been shown to help resolve ARDS inflammation in mouse models (Walter et al., 2018), a loss of Tregs might facilitate the development of COVID-19 lung immunopathology. Similarly, a reduction of γδ-T cells, a subset of T cells with apparent protective antiviral function in influenza pneumonia (Dong et al., 2018, Zheng et al., 2013), has been reported in severely sick COVID-19 patients (Guo et al., 2020, Lei et al., 2020b).