Human myeloid‐derived suppressor cell expansion during sepsis is revealed by unsupervised clustering of flow cytometric data

Abstract

Myeloid‐derived suppressor cells (MDSCs) are important regulators of immune processes during sepsis in mice. However, confirming these observations in humans has been challenging due to the lack of defined preparation protocols and phenotyping schemes for MDSC subsets. Thus, it remains unclear how MDSCs are involved in acute sepsis and whether they have a role in the long‐term complications seen in survivors. Here, we combined comprehensive flow cytometry phenotyping with unsupervised clustering using self‐organizing maps to identify the three recently defined human MDSC subsets in blood from severe sepsis patients, long‐term sepsis survivors, and age‐matched controls. We demonstrated the expansion of monocytic M‐MDSCs and polymorphonuclear PMN‐MDSCs, but not early‐stage (e)‐MDSCs during acute sepsis. High levels of PMN‐MDSCs were also present in long‐term survivors many months after discharge, suggesting a possible role in sepsis‐related complications. Altogether, by employing unsupervised clustering of flow cytometric data we have confirmed the likely involvement of human MDSC subsets in acute sepsis, and revealed their expansion in sepsis survivors at late time points. The application of this strategy in future studies and in the clinical/diagnostic context would enable rapid progress toward a full understanding of the roles of MDSC in sepsis and other inflammatory conditions.

Polymorphonuclear Cells Show Features of Dysfunctional Activation During Fatal Sepsis

“…Although it is known that circulating neutrophils and other mature PMNs are post-mitotic, we believe that these cells might be retaining a G2/M-like transcriptional profile as a result of an increased proliferation of myelocytes and pre-neutrophils in the bone marrow ( 35 ). Consistently with this hypothesis, we and others have shown that sepsis patients exhibit a higher proportion of immature PMN-myeloid-derived suppressor cells compared to healthy donors ( 36 , 37 ). Similarly, a recent study identified a population of proliferative neutrophil precursors in the spleen of healthy mice, suggesting that such progenitors can egress the bone marrow while retaining their ability to proliferate ( 38 ).…”

High levels of monocytic myeloid-derived suppressor cells are associated with favorable outcome in patients with pneumonia and sepsis with multi-organ failure

“…It is possible that either an association with mortality was missed because of sample size, or that the absence of association was genuine. In line with the second option, a recent study failed to detect an association between mortality and the expansion of PMN-MDSCs in blood sampled from sepsis patients at ICU admission and 3 days later [ 35 ].…”

Advances in Immune Monitoring Approaches for Sepsis-Induced Immunosuppression

“…It has been indicated that sepsis per se can result in the substantial augmentation of MDSCs in peripheral blood, representing one of the hallmarks of immunosuppressive response. Both circulating G-MDSCs and M-MDSCs were noted with significant increases at the early stage of sepsis, which were defined as CD14 - CD15 + and CD14 + CD15 - HLA-DR –/low , respectively ( 114 ). Nevertheless, G-MDSCs were reported to be more sensitive in discriminating septic and non-septic patients than M-MDSCs did ( 39 ).…”