A recent US study, currently available on medRxiv* preprint server, supports a beneficial rather than immunopathologic role for effector T-cells during serious infections with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – and provides several important insights for our battle against coronavirus disease 2019 (COVID-19).
The ongoing and disruptive COVID-19 pandemic, caused by the beta-coronavirus SARS-CoV-2, has shaken the world's healthcare systems and economy and claimed more than 2.22 million lives a year after its emergence.
Human adaptive immune system consists of cellular (T cell) and humoral (B cell) immunity and plays a crucial role in our defense against SARS-CoV-2. And while a coordinated interplay between the cellular and humoral arms seems to be indispensable for effective control, T cells appear to be capable of resolving the infection when B cell responses are deficient.
We know that a consistent feature of severe COVID-19 is T cell lymphopenia (i.e., an abnormally decreased level of lymphocytes in the blood), which is unlikely to merely indicate T cell sequestration in the infected lungs.
T cells as 'the most valuable players'?
T cells are likely key contributors to SARS-CoV-2 immunity; however, not much is known about the phenotypic features of SARS-CoV-2-specific T cells related to recovery from severe COVID-19. That said, some newer studies have analyzed the features of T cells recognizing SARS-CoV-2 epitopes.
Considering that these antigen-specific cells can recognize virally-infected cells and generate specific antibodies directly, they hold the most potential to show a beneficial effect on recovery from disease. They are also principal targets of vaccination endeavors.
In this study, a research group led by Dr. Jason Neidleman from the Gladstone Institutes and the University of California in San Francisco (USA) aimed to define the features of T cells from individuals hospitalized in the ICU due to COVID-19 – including some that successfully recovered and some that succumbed to the disease.
A deep phenotyping approach
In this study, the researchers have compared total and SARS CoV-2-specific T cells in mild, moderate and severe cases of COVID-19. Moreover, within the severe cases, an in-depth analysis of longitudinal specimens was conducted to pinpoint any predictive features linked to survival.
A total of 48 blood specimens from 34 individuals infected with SARS-CoV-2 have been analyzed, together with samples from 11 uninfected controls. Samples were taken from ICU patients classified as "severe cases" (68.8%), and from hospitalized patients without the need for the ICU, classified as "moderate cases" (31.2%).
The scientists implemented deep phenotyping of both total and SARS-CoV-2-specific T cells using 38-parameter CyTOF – a recently introduced technique for the characterization of T cells from convalescent individuals.
This enabled the identification of unique phenotypic characteristics of viral-specific and bystander T cells associated with recovery from severe disease, which was then paired with a comprehensive examination of the features of T cells present in the lungs of COVID-19 patients.
The role of SARS-CoV-2-specific T cells
Relative to patients who have died, individuals in this study that recovered from severe forms of COVID-19 presented with elevated numbers of SARS-CoV-2-specific T cells capable of honing a physiological response known as homeostatic proliferation.
More specifically, the researchers observed an increased number of CD8-positive transitional memory T-cells in patients with mild symptoms and a higher number of activated, PD1-expressing T-cells in patients with severe symptoms.
Conversely, in fatal cases of COVID-19, there was an elevated number of SARS-CoV-2-specific regulatory T cells and a time-dependent upsurge in activated bystander CXCR4+ T-cells (the latter subset of cells is also regarded as "extrafollicular" helper T cells).
When all results are taken into account, this study represents a model in which lung-homing T cells activated via bystander effect contribute to immunopathology, whereas a non-suppressive and robust SARS-CoV-2-specific T cell response controls pathogenesis and stimulates recovery from severe COVID-19.
Implications for vaccination efforts
In a nutshell, this study's findings support a favorable rather than immunopathologic role for effector SARS-CoV-2-specific T cells during the severe acute infection, together with promoting recovery from COVID-19.
"Taking into consideration the longevity of SARS-CoV-2-specific T cells, our results suggest that strategies to boost the effector functions of SARS-CoV-2-specific T cells, including by vaccination, will be beneficial for decreasing COVID-19 mortality and helping to end this devastating pandemic", say the authors of this medRxiv study.
In any case, since this study was correlative and phenotypical in nature, follow-up functional assays will be needed to establish any causal effect, as well as studies on larger cohorts of infected individuals.
*Important Notice
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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