Fewer, Functionally Exhausted T Cells Observed in Severe COVID-19

Fewer and functionally "exhausted" T cells can accompany the increase in cytokines associated with coronavirus 2019 (COVID-19), and could be as important an indicator for urgent intervention as reduced respiratory function, according to a new study published in Frontiers in Immunology.

"We should pay more attention to T cell counts and their function, rather than respiratory function of patients," Yongwen Chen, PhD, Institute of Immunology, PLA, Third Military Medical University, Chongqing, China, said in a statement. "More urgent, early intervention may be required in patients with low T lymphocyte counts.”

Chen and colleagues conducted a retrospective assessment of lymphocyte and T cell counts, and serum cytokine concentrations for 499 patients who were admitted with a diagnosis of COVID-19 to 2 hospitals in Wuhan, China between December 2019 and January 2020. The laboratory values were compared to those from 40 healthy controls, who had come to the hospitals for routine physical examination.

Forty-three of the patients were admitted to the intensive care unit (ICU) because of requirement for high-flow nasal cannula or mechanical ventilation. Analysis of T cell counts was also stratified among 212 patients who were not initially admitted to the ICU, based on the progression to 4 levels of clinical outcomes (151 mild/moderate; 40 severe; 13 critical; 8 deceased).

Peripheral blood samples from 14 patients and 3 healthy controls were also processed to analyze the frequency and cell number of total CD4⁺ and CD8⁺ T cells, and for the expression of exhaustion markers on the surface of the T cells: PD-1 and TIM-3. In addition, 3 patients were followed prospectively during inpatient care, with the expression of PD-1 and Tim-3 determined during the progress of their illness.

"T cell exhaustion is a state of T cell dysfunction that arises during many chronic infections and cancer," Chen and colleagues explained. "It is defined by poor effector function, sustained expression of inhibitory receptors, and a transcriptional state distinct from that of functional effector or memory T cells."

Investigators found 75.75%, 75.95%, and 71.54% of patients with "remarkably" low total T cell counts, CD4⁺, and CD8⁺ T cell counts, respectively. Among patients with milder disease in the non-ICU group, the median value of total, CD4⁺, and CD8⁺ T cell counts were 652, 342, and 208 respectively. In contrast, those median values in the ICU group were 261, 198, and 64.3, respectively.

The investigators noted that an expression of angiotensin converting enzyme 2 (ACE2), the predicted receptor of SARS-CoV-2 virus, was not found on T cells, suggesting that the depressed T counts were not likely to have been caused by direct infection of T cells.

Instead, they confirmed that the reduced T cell counts were negatively correlated with increased levels of IL-10, IL-6 and TNF-α. Further, they found that cytokines were reduced, and T cell counts recovered as patients recovered from the illness.

"The phenomena suggests that the decrease of T cells seen in COVID-19 patients may be the result of high serum concentration of TNF- α, IL-6, and IL-10 negatively regulating T cell survival or proliferation.

In addition to decreased T cell count, the researchers determined that the markers of T cell function progressively increased with greater disease severity. Although there were relatively low percentages of PD-1 and Tim-3 expression on the surfaces of CD4⁺ and CD8⁺ T cells in the prodromal stage of disease, high percentages of Tim-3 expression were observed on CD4⁺ , and of PD-1 and Tim-3 on CD8⁺ T cells in ICU patients.

"These results demonstrated that T cells are exhausted in COVID-19 patients during SARS-CoV-2 infection," Chen and colleagues indicated.

Their findings also suggest opportunities for intervention, they indicate. The association of reduced T cells with increased cytokines, for example, could support research with agents like tocilizumab, an anti-IL-6 receptor monoclonal antibody which was developed for arthritis. They also anticipate that progress with antiviral treatments such as remdesivir could yield agents that interrupt the deleterious effects of COVID-19 on T cell function.

"The application of potent antiviral treatments to prevent the progression to T cell exhaustion in susceptible patients may thus be critical to their recovery," Chen and colleagues wrote.