Storm of soluble immune checkpoints associated with disease severity of COVID-19

Abstract

As the outbreak of coronavirus disease 2019 (COVID-19) turns into a pandemic, it has literally caused a worldwide public health crisis. Progressive lymphopenia, especially in T cells, was a prominent clinical feature of severe COVID-19 in addition to dyspnea, hypoxemia, acute respiratory distress, and cytokine release syndrome.1 Recently, several studies revealed a correlation between T cell depletion and increased expression levels of several inhibitory checkpoint molecules on T cells in severe COVID-19 cases.2 Classically, inhibitory checkpoint molecules have been documented as key factors for regulating T cell exhaustion in a variety of chronic viral infections and tumors. Recent studies further implied a pivotal role of inhibitory checkpoint molecules in the pathophysiology of acute viral infections, such as Ebola virus or hantavirus infection. Of note, soluble isoforms of checkpoints can be produced by cleavage of membrane-bound proteins or by alternative splicing of mRNA and competitively regulate the functions of their membrane-bound counterparts.3 Thus it is of great interest to determine whether soluble checkpoint molecules are involved in immune regulation and severity of COVID-19.