Exhausted T cells linked to increased risk of COVID-19 mortality

T cells are an essential player in the immune system and have been integral to recovering from severe COVID-19 infection. However, some T cells may be more helpful than others.

New research led by Nadia R. Roan of Gladstone Institutes and the University of California, San Francisco, finds a correlation between high numbers of inflammatory CXCR4+ T cells and regulatory T cells specific to SARS-CoV-2 and dying from infection. In contrast, people who recovered from severe COVID-19 illness were more likely to have many SARS-CoV-2-specific T cells that perform homeostatic proliferation.

The researchers write:

“Our findings overall support a beneficial rather than immunopathologic role of effector SARS-CoV-2-specific T cells during severe acute infection.”

Based on the results, they suggest COVID-19 strategies should be geared towards increasing the effector functions of SARS-CoV-2-specific T cells — such as getting vaccinated with an approved vaccine.

The study “Distinctive features of SARS-CoV-2-specific T cells predict recovery from severe COVID-19” was published in the journal Cell Reports.

How they did it

The study looked at the features of SARS-CoV-2 T cells, including the type of T cells and number of T cells present in 34 hospitalized patients having either mild, moderate, or severe COVID-19 infections. Severe cases came from hospitalized patients in the ICU for COVID-19 infection and included people who recovered and people who died from the illness.

The researchers took a deeper dive into the severe COVID-19 cases with a longitudinal study. The goal was to characterize T cell features better and predict who would survive or not survive severe COVID-19 illness.

T cell differences between mild and severe COVID-19 illness

Mild COVID-19 infection was associated with high levels of CD8+ transitional memory (TTM) cells.

Severe infection had high levels of activated, PD1-expressing T cells. Memory T cells were also elevated among patients with severe illness. Although the researchers suggest the boost in memory T cells were more likely due to age.

CD4+ Tem cells increased in severe cases, but CD4+ Temra cells decreased.

The findings showed a significant boost in exhausted SARS-CoV-2-specific T cells in patients with severe infection. The researchers suggest that T cell exhaustion, along with proof of elevated transcript levels of multiple exhaustion markers such as PD1, shows that T cell exhaustion correlates with disease severity.

Coexpression of PD1 with the Fas receptor CD95, involved in cell death, was observed along with more elevated PD1+CD95+ T cells in severe than mild cases.

A notable finding was that the number of CXCR4+CD69+ T cells decreased throughout recovery in patients who survived COVID-19. However, these T cells increased over time in people who died.

The researchers suggest that CXCR4 antagonists —such as AMD3100 — could help prevent CXCR4-driven T cell infiltration and potentially decrease a patient’s COVID-19 mortality risk.

Characteristics of T cell response in COVID-19 recovery

Results showed that recovering from COVID-19 involves an elevated boost in SARS-CoV-2 specific T cell response, which increases further before recovery.

“These data suggest that SARS-CoV-2-specific T cells are protective during severe COVID-19 and are in line with a number of other reports, including a recent report of greater expansion of SARS-CoV-2-specific T cells during moderate than severe COVID-19; the finding that antigen-specific T cells against SARS-CoV-1, a close relative of SARS-CoV-2, are protective in mouse infection models; and a recent study demonstrating SARS-CoV-2-specific T cell responses, as defined by AIM markers, to be associated with less severe disease,” concluded the team.

Study limitations

The study results were derived from a very small cohort of patients with severe COVID-19 disease. The researchers explain the small sample size was necessary for deep phenotyping of SARS-CoV-2-specific T cells. However, it could have caused researchers to miss any other extraneous factors that may have contributed to COVID-19 mortality, such as demographic differences. Future studies with larger patient cohorts are encouraged to confirm this study’s results.

Another limitation involved using peptide stimulation to find SARS-CoV-2-specific cells. The stimulation was limited to 6 hours, but it is possible for T cells to respond immediately after an antigen encounter rather than at baseline. The analysis also narrowed down the focus to T cells from the blood, although there were activated CXCCR4+ T cells in the lungs of patients with COVID-19 infection.

The researchers looked at immune responses in T cells that were specific to SARS-CoV-2’s spike protein. T cells recognizing the spike protein tend to produce some CD8+ T cell response. However, T cells and other players in the immune system have also been stimulated by the presence of other proteins beyond the spike protein. Future work should look into characterizing T cell response from the presence of various SARS-CoV-2 proteins.

Journal reference:
Jocelyn Solis-Moreira

Written by

Jocelyn Solis-Moreira

Jocelyn Solis-Moreira graduated with a Bachelor's in Integrative Neuroscience, where she then pursued graduate research looking at the long-term effects of adolescent binge drinking on the brain's neurochemistry in adulthood.


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