Cytokine storms may impact the severity of COVID-19 cases by lowering T-cell populations -- information that can be used to guide the development of new treatments, according to a study published in Frontiers in Immunology on May 1.
The immune response against virus-infected cells often requires activation of cytotoxic T cells to clear infection. Therefore, a boost in number and function of T cells -- a specialized type of white blood cell -- should help patients recover from COVID-19, the acute respiratory illness caused by SARS-CoV-2. A recent study revealed that most patients with COVID-19 displayed low circulating white blood cell (lymphocyte) counts, but the reason for this is unknown. So, researchers studying the novel coronavirus in China retrospectively analyzed over 500 clinical samples from COVID-19 patients in Wuhan, China, from December 2019 to January 2020.
"Considering T cells' central role of response against viral infections, especially in the early stage when antibodies are not boosted yet, we took the T cells as our focal point," said senior author Yongwen Chen, PhD, of Third Military Medical University in China, in a statement.
The researchers found significant decreases in both cluster of differentiation 4 (CD4)+ and CD8+ T cells in a majority of COVID-19 patients. Of the patients, 76% had low total T-cell counts, and patients with severe cases had significantly lower T-cell counts compared with mild COVID-19 cases. Moreover, the lowest T-cell numbers were observed in patients who were older than 60 years.
To explore the impact of cytokine signaling in COVID-19 cases, the researchers also examined serum concentrations of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukin-2 (IL-2), IL-4, IL-6, and IL-10. They observed that only TNF-α, IL-6, and IL-10 levels were significantly increased but also were negatively correlated to T-cell counts. These results indicate that the decrease in T cells in COVID-19 patients may be the result of high serum concentrations of TNF-α, IL-6, and IL-10 that negatively regulate T-cell survival or proliferation.
Importantly, the researchers noted that the secretion of cytokines in patients with COVID-19 does not originate from T cells but rather that the cytokine storm, in turn, may promote apoptosis or necrosis of T cells. Cytokine storm is a phenomenon of excessive inflammatory reaction in which cytokines are rapidly produced in large amounts in response to microbial infection.
Both TNF-α and IL-6 have been previously implicated in T-cell apoptosis and chronic inflammation during infection, respectively. The authors suggested that cytokines might be produced by monocytes or macrophages, but further investigation is needed to confirm this hypothesis.
T-cell exhaustion is a state of T-cell dysfunction and is defined by poor effector function and prolonged expression of inhibitory receptors such as programmed cell death 1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3). Exhaustion phenotypes were observed as associated with PD-1 and TIM-3 expression in both CD8+ and CD4+ T cells in patients with COVID-19, especially as the disease progressed. Patients with high levels of IL-10, PD-1, and TIM-3 expression following SARS-CoV-2 infection suggests that IL-10 may be responsible for a state of T-cell exhaustion during COVID-19.
Overall, the authors concluded that persistent stimulation of lymphocytes by the SARS-CoV-2 virus may lead to T-cell exhaustion and therefore loss of cytokine production and related ability to clear viral infections in patients with COVID-19. They noted that tocilizumab is an existing drug that may be effective, but they added that it needs to be investigated in the context of the novel coronavirus. (Tocilizumab is marketed under the brand name Actemra by Roche for rheumatoid arthritis.) Antiviral treatments, such as remdesivir (Gilead), may also prevent the progression of T-cell exhaustion, but all new treatments will require further study.