key: cord-0983666-o5f0woxe
authors: Chen, Jiezhong; Vitetta, Luis
title: Increased PD-L1 expression may be associated with the cytokine storm and CD8 (+) T-cell exhaustion in severe COVID-19
date: 2021-02-01
journal: J Infect Dis
DOI: 10.1093/infdis/jiab061
sha: ff825fb9bd721af6fa84dcb41a8fc62ad56b0ab8
doc_id: 983666
cord_uid: o5f0woxe

nan

M a n u s c r i p t 2 Severe Covid-19 is characterised by both a cytokine storm and lymphopenia with reduced frequency of CD4 + and CD8 + T-cells [1] . CD8 + cytotoxic T-lymphocyte cells play a key role in virus clearance, thereby decreasing viral replication and viral load [2] . Numerous clinical studies have characterized the changes of CD8 + T-cells in mild and severe COVID-19 patients that expose the importance of CD8 + T-cells in the progression of Covid-19. However, the mechanisms by which the changes in CD8 + T-cells that ensue are not well elucidated. The study by Vitte et al found that increased PD-L1 in basophils, eosinophils, monocytes and NK cells in severe COVID-19 patients, particularly the expression of PD-L1 in basophils and eosinophils, were correlated with COVID-19 severity [3] . These findings could provide a plausible explanation for CD8 + T-cell exhaustion in COVID-19. The cytokine storm may be responsible for increased PD-L1 expression, which leads to CD8 + T-cell exhaustion.

However, the study failed to identify the importance of lymphopenia in COVID-19 severity, probably due to small sample numbers (89% in severe cases vs 71% in mild cases, not statisticallysignificant).

Similarly, the cytokine storm was also not well characterized and correlated with PD-L1 expression in severe COVID-19.

In severe COVID-19, blood levels of proinflammatory cytokines such as IL-6, IL-17 and TNF-alpha are significantly increased together with increased activity of macrophages and neutrophils [4] . These cytokines could be the cause for the increased expression of PD-L1 on the surfaces of immune cells in COVID-19. It is well known that PD-L1 expression is regulated by various signalling pathways which are activated by proinflammatory cytokines (Fig. 1) [5] . For example, IL-6 can activate the STAT3 signalling pathway, which in turn increases the expression of PD-L1 [5] . TNF-alpha can activate PI3K/Akt and NF-kB signalling pathways that also upregulate PD-L1 expression. These cytokines may have a synergistic effect on the expression of PD-L1. The PD-L1/PD-1 axis is a major regulator of CD8 + T-cell functionalities and survivability. PD-L1 binds to and activates PD-1, resulting in CD8 + T-cell dysfunction and apoptosis [5] .

A c c e p t e d M a n u s c r i p t 3 Elucidaton of a cytokine storm/PD-L1/PD-1/CD8 T-cell exhaustion axis may have important therapeutic implications. Inhibition of proinflammatory cytokines and activated signalling pathways that increase expression of checkpoint molecules may also be effective for recovering CD8 + T-cells ( Fig. 1) . A recent study has correlated pro-inflammatory cytokines with changes of CD8 + T-cells in COVID-19 [6] . Furthermore, anti-IL-6 treatment of COVID-19 patients increased CD8 + T-cell frequency and functionalities [7] . In addition, blockade of PD-L1/PD-1 could be an approach that recovers CD8 + T-cell numbers and functionalities. Also, anti-inflammatory cytokines may be used to decrease the inflammatory status and recover CD8 + T-cells. For example, IL-15 has been proposed for the treatment of COVID-19 [4] . IL-15 can increase CD8 + T-cell functionalities, CD8 + memory Tcells and "memory-like" naive CD8 + T-cells [8, 9] . While additional studies are required to further understand the mechanisms of CD8 + T-cell exhaustion, it is plausible that approaches that target proinflammatory cytokines, activated signals, PD-L1/PD-1 could significantly contribute to the recovery of the repertorie of CD8 + T-cells in fulminant Covid-19 cases (Fig. 1) .

M a n u s c r i p t We received no external funds for this work.

We declare that we have no conflicts of interest.

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A c c e p t e d M a n u s c r i p t 6 A c c e p t e d M a n u s c r i p t