Generation and functional characterization of MDSC-like cells

Abstract

Myeloid-derived suppressor cells (MDSC) are critical in regulating immune responses by suppressing antigen presenting cells (APC) and T cells. We previously observed that incubation of peripheral blood monocytes with interleukin (IL)-10 during their differentiation to monocyte-derived dendritic cells (moDCs) results in the generation of an APC population with a CD14 C HLA-DR low phenotype (IL-10-APC) with reduced stimulatory capacity similar to human MDSC. Co-incubation experiments now revealed that the addition of IL-10-APC to moDC caused a reduction of DC-induced T-cell proliferation, of the expression of maturation markers, and of secreted cytokines and chemokines such as TNF-a, IL-6, MIP-1a and Rantes. Addition of IL-10-APC increased the immunosuppressive molecule osteoactivin and its corresponding receptor syndecan-4 on moDC. Moreover, CD14 C HLA-DR low MDSC isolated from healthy donors expressed high levels of osteoactivin, which was even further upregulated by the auxiliary addition of IL-10. Using transcriptome analysis, we identified a set of molecules and pathways mediating these effects. In addition, we found that IL-10-APC as well as human isolated MDSC expressed higher levels of programmed death (PD)-1, PD-ligand-1 (PD-L1), glucocorticoid-induced-tumor-necrosis-factor-receptor-related-protein (GITR) and GITR-ligand. Inhibition of osteoactivin, syndecan-4, PD-1 or PD-L1 on MDSC by using blocking antibodies restored the stimulatory capacity of DC in co-incubation experiments. Activation of MDSC with Dectin-1 ligand curdlan reduced the expression of osteoactivin and PD-L1. Our results demonstrate that osteoactivin/syndecan-4 and PD-/PD-L1 are key molecules that are profoundly involved in the inhibitory effects of MDSC on DC function and might be promising tools for clinical application.

Induction of a regulatory myeloid program in bacterial sepsis and severe COVID-19

“…In fact,~50% genes expressed specifically in monocytic MDSCs vs monocytes, as found in a recent study 5 , overlap with MS1-specific marker genes ( Supplementary Fig. 10 ), though our MS1 signature contains many additional genes, suggesting that we have identified a more pure MDSC-like population; however, analysis of additional contexts in which MDSCs are found is warranted 43,[54][55][56] . We also demonstrate that MS1 cells have an anti-inflammatory effect on endothelial and epithelial cells, raising the possibility that MS1 contributes to the pathology of these cell types during bacterial sepsis and severe COVID-19.…”

Distinct alterations of CD68+CD163+ M2-like macrophages and myeloid-derived suppressor cells in newly diagnosed primary immune thrombocytopenia with or without CR after high-dose dexamethasone treatment

“…Myeloid-derived suppressor cells (MDSCs), generally recognized as circulating immature myeloid cells with remarkable immunosuppressive properties [ 8 ], have been verified to contribute to the inactivation of T-cells and antigen presenting cells during various diseases, particularly in cancer [ 9 , 10 ]. The role of MDSCs in autoimmune diseases is just starting to be elucidated.…”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…48,261,[267][268][269][270][271][272][273] In this setting, the profiling of T REG cells is being performed in most cases to estimate the ability of cyclophosphamide to specifically target these immunosuppressive cells. [274][275][276] It will be interesting to see whether the peripheral profile (in terms of abundance and activation status) of CD4…”