University Of California Study Shows That Exhausted T Cells Are Linked To Increased Risk Of COVID-19 Death

A new study by researchers from the University of California-San Francisco and the Gladstone Institutes-California has shown that exhausted T cells are linked to increased risk of COVID-19 mortality.

Despite T cells being key players in SARS-CoV-2 immunity, little is known about the phenotypic features of SARS-CoV-2-specific T cells associated with recovery from the COVID-19 disease.
 
The study team analyzed T cells from 34 individuals with COVID-19 with severity ranging from mild (outpatient) to critical, culminating in death.
 
Interestingly it was found that relative to individuals who succumbed, individuals who recovered from severe COVID-19 harbor elevated and increasing numbers of SARS-CoV-2-specific T cells capable of homeostatic proliferation.
 
However in contrast, fatal COVID-19 cases display elevated numbers of SARS-CoV-2-specific regulatory T cells and a time-dependent escalation in activated bystander CXCR4+ T cells, as assessed by longitudinal sampling.
 
Along with the demonstration of increased proportions of inflammatory CXCR4+ T cells in the lungs of individuals with severe COVID-19, the study findings support a model where lung-homing T cells activated through bystander effects contribute to immunopathology, whereas a robust, non-suppressive SARS-CoV-2-specific T cell response limits pathogenesis and promotes recovery from severe COVID-19.
 
The key takeaways from the study are:
 
-1) Dysfunctional spike-specific T cells are characteristic of severe COVID-19
 
-2) Spike-specific CD127+ Th1 cells are increased in survivors of severe COVID-19
 
-3) Spike-specific Treg cells and IL6+ CD8+ T cells are increased in fatal COVID-19
 
-4) Escalation of activated lung-homing CXCR4+ T cells is associated with fatal COVID-19.
 
The study findings were published in the peer reviewed journal: Cell Reports
https://www.cell.com/cell-reports/fulltext/S2211-1247(21)00827-5
 
Typically 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.
 
The study team however found 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, individuals who recovered from severe COVID-19 illness were more likely to have many SARS-CoV-2-specific T cells that perform homeostatic proliferation.
 
Corresponding author Dr Kara L. Lynch from the department of Laboratory Medicine, University of California- San Francisco told Thailand Medical News,  “Our findings overall support a beneficial rather than immunopathologic role of effector SARS-CoV-2-specific T cells during severe acute infection.”
 
From the study findings, the study team suggest COVID-19 strategies should be geared tow ards increasing the effector functions of SARS-CoV-2-specific T cells ie such as getting vaccinated with an approved vaccine.
 
The researchers 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 study team 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.
 
The team observed T cell differences between mild and severe COVID-19 illness.
 
It was found that mild COVID-19 infection was associated with high levels of CD8+ transitional memory (TTM) cells.
 
However severe infection had high levels of activated, PD1-expressing T cells. Memory T cells were also elevated among patients with severe illness. The researchers however suggest the boost in memory T cells were more likely due to age.
 
Interestingly CD4+ Tem cells increased in severe cases, but CD4+ Temra cells decreased.
 
The study 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.
 
Also 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 significant 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 study team suggests that CXCR4 antagonists could help prevent CXCR4-driven T cell infiltration and potentially decrease a patient’s COVID-19 mortality risk.
 
Examples of known CXCR4 inhibitors include Plerixafor, a drug used for certain types of cancers.
 
The study findings showed that recovering from COVID-19 involves an elevated boost in SARS-CoV-2 specific T cell response, which increases further before recovery.
 
Dr Lynch told Thailand Medical News, “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.”
 
The researchers however acknowledged that the study had certain limitations. The findings were derived from a very small cohort of patients with severe COVID-19 disease.
 
However the study team explains the small sample size was necessary for deep phenotyping of SARS-CoV-2-specific T cells but 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.
 
Also 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 study team 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.
 
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