Functional myeloid-derived suppressor cells expand in blood but not airways of COVID-19 patients and predict disease severity

Abstract

The immunopathology of COVID-19 remains enigmatic, exhibiting immunodysregulation and T cell lymphopenia. Monocytic myeloid-derived suppressor cells (M-MDSC) are T cell suppressors that expand in inflammatory conditions, but their role in acute respiratory infections remains unclear. We studied blood and airways of COVID-19 patients across disease severity at multiple timepoints. M-MDSC frequencies were elevated in blood but not in nasopharyngeal or endotracheal aspirates of COVID-19 patients compared to controls. M-MDSCs isolated from COVID-19 patients suppressed T cell proliferation and IFNγ production partly via an arginase-1 (Arg-1) dependent mechanism. Furthermore, patients showed increased Arg-1 and IL-6 plasma levels. COVID-19 patients had fewer T cells, and displayed downregulated expression of the CD3ζ chain. Ordinal regression showed that early M-MDSC frequency predicted subsequent disease severity. In conclusion, M-MDSCs expand in blood of COVID-19 patients, suppress T cells and strongly associate with disease severity, suggesting a role for M-MDSCs in the dysregulated COVID-19 immune response.

Myeloid cell dynamics correlate with clinical outcomes of severe coronavirus disease 2019

“…Although M-MDSC and PMN-MDSC subsets remained unchanged in the early phase, the frequencies of PMN-MDSCs, rather than M-MDSCs, dramatically increased in the late phase of severe COVID-19 ( Fig. 1b, 1c, 2a, and 2b), reproducing ndings in recent publications [17][18][19][20][21][22] . Further extending previous ndings, we found that the increase in PMN-MDSCs was transient, and the frequencies of PMN-MDSCs returned to basal levels during the recovery phase before discharge (Fig.…”

“…They are equipped with several immunosuppressive molecules; however, whether they are bene cial or detrimental to the clinical outcomes of cancer, obesity, and chronic infectious diseases remains unclear 8,9 . In agreement with this, several groups have recently reported the expansion of MDSC subsets in severe COVID-19 patients [16][17][18][19][20][21][22] ; however, the link between MDSC subsets and clinical outcome remains to be addressed, owing to limitations in experimental design. By separately analyzing survivors and non-survivors of severe COVID-19, we revealed the expansion of the PMN-MDSC subset as a survival-speci c event that is associated with recovery from the disease.…”

“…Perhaps transient and more effective immunosuppression by PMN-MDSCs is necessary for host survival in severe COVID-19. Alternatively, as claimed by other groups, the expansion of M-MDSCs could contribute to the immune imbalance described in COVID-19, possibly favoring disease progression 21 . Thus, the balance between PMN-MDSC and M-MDSC subsets might be crucial for regulating disease severity and could be associated with prognosis.…”

“…In addition, elevated levels of interleukin (IL)-6 and IL-8, well-known inducers of MDSCs 11-13 , are observed in severe cases of COVID-19 14,15 . This information suggests a possible link between MDSCs and COVID-19. The expansion of MDSCs and MDSC-like cells has been repeatedly observed in severe COVID-19 patients by several research groups from different countries [16][17][18][19][20][21][22] . However, to gain insight into the roles of MDSCs in COVID- 19, it is important to analyze the cell subsets in association with different clinical outcomes (e.g.…”

Myeloid cell dynamics correlate with clinical outcomes of severe coronavirus disease 2019

“…Although M-MDSC and PMN-MDSC subsets remained unchanged in the early phase, the frequencies of PMN-MDSCs, rather than M-MDSCs, dramatically increased in the late phase of severe COVID-19 ( Fig. 1b, 1c, 2a, and 2b), reproducing findings in recent publications [17][18][19][20][21][22] . Further extending previous findings, we found that the increase in PMN-MDSCs was transient, and the frequencies of PMN-MDSCs returned to basal levels during the recovery phase before discharge (Fig.…”