Proinflammatory Cytokines Secreted by T Cells During COVID-19
Hyperinflammatory condition mediated by cytokines, chemokines and associated proinflammatory molecules which are secreted by both innate and adaptive immune cells. However, during COVID-19, the relative contribution of adaptive immune cells towards proinflammatory molecules is still emerging, while the published studies suggest a complex interplay. Profiling of 21 cytokines and chemokines in 39 patients and 24 healthy controls revealed increased levels of TH1 specific cytokines like IFN-γ, IL-2, and IL-12, and TH17 specific IL-17 in peripheral blood. In comparison to the mild cases (n = 19), patients with severe disease (n = 10) condition had increased levels of these cytokines. The limitation of this study was that the median age of severe cases was higher than in mild cases (Song et al., 2020).
Similarly, Zhou et al. (2020b) reported hyperactivated TH1 cell response with increased secretion of IFN-γ, GM-CSF, and IL-6 and with more robust expression in ICU cases than non-ICU. Considering the age, gender and other associated factors, a large number of other studies have now confirmed that COVID-19 patients have increased levels of TH1 specific cytokines, with more robust levels seen in severe than mild cases (Huang C. et al., 2020; Xu Z. et al., 2020; Zhou et al., 2020b). Similarly, CD8+ T cell-specific cytokines increased in COVID-19 patients, more pronounced in severe than mild condition (Zhou et al., 2020b). Increased expression of GM-CSF was found in CD8+ T cells from ICU patients than non-ICU, while no difference was observed in IL-6 and TNF-α levels. PBMCs derived from COVID-19 patients and stimulated in vitro showed an increase in expression of CCL2, CXCL10, Eotaxin, and IL-1RA, and stimulation of CD8+ T cells were associated with an increase in IFN-γ levels, which indicates the functional responsiveness of these cells (Mathew et al., 2020). These studies thus suggest a robust activation of TH1 specific and CD8+ T cells in COVID-19 patients.
On the contrary, there are studies which show decreased cytokine expression by T cells in severe COVID-19 cases. A study by Zheng H.Y. et al. (2020) showed a lower expression of IFN-γ, IL-2, and TNF-α in CD4+ T cells derived from severe cases. Similarly, a decrease in IL-2+ CD8+ and IFN-γ+ CD8+ cells was also observed (Diao et al., 2020). Although most studies point toward the robust activation and release of proinflammatory cytokines by CD4+ and CD8+ T cells, the discrepancy in latter studies could attribute to the functional exhaustion of these cells, which will we will discuss in section “Lymphocytopenia During COVID-19.”
Besides the presence of TH1 cytokines, TH2 cytokines like IL-4 and IL-5 and TH17 specific IL-17 were reported in some studies (Han et al., 2020; Huang C. et al., 2020; Song et al., 2020; Tan L. et al., 2020b; Xu Z. et al., 2020). The presence of TH2 cytokines usually seen in mild cases may be accounted for by the presence of other respiratory conditions with TH2 specific response (Laing et al., 2020). Overall, all these studies point toward the increased secretion of proinflammatory molecules by T lymphocytes in COVID-19, albeit with a heterogeneous response, which may be due to the variation in the age of the patients studied, different sampling times and presence of the comorbid condition, which needs further investigation.