Functional monocytic myeloid-derived suppressor cells increase in blood but not airways and predict COVID-19 severity
Sara Falck-Jones, … , Anna Färnert, Anna Smed-Sörensen
Sara Falck-Jones, … , Anna Färnert, Anna Smed-Sörensen
Published January 25, 2021
Citation Information: J Clin Invest. 2021;131(6):e144734. https://doi.org/10.1172/JCI144734.
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Research Article COVID-19 Immunology

Functional monocytic myeloid-derived suppressor cells increase in blood but not airways and predict COVID-19 severity

Abstract

The immunopathology of coronavirus disease 2019 (COVID-19) remains enigmatic, causing immunodysregulation and T cell lymphopenia. Monocytic myeloid-derived suppressor cells (M-MDSCs) are T cell suppressors that expand in inflammatory conditions, but their role in acute respiratory infections remains unclear. We studied the blood and airways of patients with COVID-19 across disease severities at multiple time points. M-MDSC frequencies were elevated in blood but not in nasopharyngeal or endotracheal aspirates of patients with COVID-19 compared with healthy controls. M-MDSCs isolated from patients with COVID-19 suppressed T cell proliferation and IFN-γ production partly via an arginase 1–dependent (Arg-1–dependent) mechanism. Furthermore, patients showed increased Arg-1 and IL-6 plasma levels. Patients with COVID-19 had fewer T cells and downregulated expression of the CD3ζ chain. Ordinal regression showed that early M-MDSC frequency predicted subsequent disease severity. In conclusion, M-MDSCs expanded in the blood of patients with COVID-19, suppressed T cells, and were strongly associated with disease severity, indicating a role for M-MDSCs in the dysregulated COVID-19 immune response.

Authors

Sara Falck-Jones, Sindhu Vangeti, Meng Yu, Ryan Falck-Jones, Alberto Cagigi, Isabella Badolati, Björn Österberg, Maximilian Julius Lautenbach, Eric Åhlberg, Ang Lin, Rico Lepzien, Inga Szurgot, Klara Lenart, Fredrika Hellgren, Holden Maecker, Jörgen Sälde, Jan Albert, Niclas Johansson, Max Bell, Karin Loré, Anna Färnert, Anna Smed-Sörensen

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Figure 2

Frequency of respiratory and blood M-MDSCs in patients with COVID-19, patients with influenza, and HCs.

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Frequency of respiratory and blood M-MDSCs in patients with COVID-19, pa...
(A) Gating strategy to identify M-MDSCs by flow cytometry. From live, single CD45+ leukocytes, cells expressing lineage markers (CD3, CD19, CD20, CD56, CD66abce) and HLA-DR were excluded and CD14+ M-MDSCs identified. (B) M-MDSC frequency per live CD45+ cells in blood and NPAs. HCs (blue): n = 12 (blood), n = 7 (NPAs). Patients with influenza (open circles): n = 19 (blood), n = 9 (NPAs). COVID-19 patients (solid circles): n = 140 (blood), n = 28 (NPAs). The dots are color-coded according to peak disease severity. (C) Peak frequency of blood M-MDSCs per live CD45+ cells across disease severity. HCs (blue): n = 12. Patients with COVID-19 (color-coded by peak disease severity): mild, n = 19; moderate, n = 53; severe, n = 56; fatal, n = 12. (D) Blood M-MDSC frequencies over time in patients with COVID-19: mild, n = 17; moderate, n = 53; severe, n = 56; fatal, n = 12. Line shows the locally estimated scatterplot smoothing (LOESS) with shaded 95% CI (fatal group wide CI, not presented). (E) Frequency of blood M-MDSCs in paired acute and convalescent samples from patients with COVID-19 (n = 6). (F) M-MDSC frequency in blood, NPA, and ETA samples from patients with severe (red, n = 16) and fatal (gray, n = 4) COVID-19. (G–I) Surface expression of (G) CD62L, (H) CD86, and (I) CCR2 on M-MDSCs in blood, NPAs, and ETAs from HCs (blue, NPAs n = 7, PBMCs n = 11) and COVID-19 patients (black, NPAs n = 25, ETAs n = 19, PBMCs n = 69). (J) Frequency of PMN-MDSCs of live CD45+ cells in blood from patients with COVID-19. HCs: n = 12. Patients with COVID-19: mild, n = 11; moderate, n = 47; severe, n = 42; and fatal, n = 8. (K) Frequency of blood PMN-MDSCs in paired acute and convalescent samples from patients with COVID-19 (n = 6). (B, C, and F–J) Comparisons of M-MDSC frequencies were performed using the nonparametric Kruskal-Wallis test with Dunn’s post hoc multiple-comparison test. In the strip charts, group medians are presented as horizontal lines and individual patients as jitter points.