Prostaglanin-E2 Potentiates the Suppressive Functions of Human Mononuclear Myeloid-Derived Suppressor Cells and Increases Their Capacity to Expand IL-10-Producing Regulatory T Cell Subsets

Abstract

Myeloid-derived suppressor cells (MDSC) emerged as major factors driving the tumor progression due to numerous immunosuppressive mechanisms they possess. Prostaglandin (PG)E2 is shown critical for the induction of MDSC and their suppressive functions in vivo, but it is poorly understood how it affects the capacity of MDSC to induce different subsets of regulatory T cells (Treg). By using a novel protocol for the generation of mononuclear (M)-MDSC, we showed that PGE2 potentiates the GM-CSF/IL-6-dependent induction of CD33+CD11b+HLA-DR−CD14+ M-MDSC in vitro. PGE2 diminished the capacity of GM-CSF/IL-6 M-MDSC to produce proinflammatory cytokines upon activation and augmented their capacity to produce IL-27, IL-33, and TGF-β. These results correlated with an increased potential of GM-CSF/IL-6/PGE2 M-MDSC to suppress T cell proliferation, expand alloreactive Th2 cells, and reduce the development of alloreactive Th17 and cytotoxic T cells. Interestingly, GM-CSF/IL-6/PGE2 M-MDSC displayed a lower capacity to induce TGF-β-producing FoxP3+ regulatory Treg compared to GM-CSF/IL-6 M-MDSC, as a consequence of reduced IDO-1 expression. In contrast, GM-CSF/IL-6/PGE2 M-MDSC potentiated IL-10 production by CD8+T, Th2, and particularly CD4+FoxP3− type 1 Treg, the latter of which depended on ILT3 and ILT4 expression. Cumulatively, PGE2 potentiated the suppressive phenotype and functions of GM-CSF/IL-6-induced M-MDSC and changed the mechanisms involved in Treg induction, which could be important for investigating new therapeutic strategies focused on MDSC-related effects in tumors and autoimmune diseases.

Contained Mycobacterium tuberculosis infection induces concomitant and heterologous protection

“…Samples were scored on a 0-4 extent scale (0 = normal; 1 = <5%; 2 = 6-30%, 3 = 31-60%, 4 = >60%) for the fraction of the lung affected in any manner (Extent 1) and for the fraction of the lung affected in the worst manner (Extent 2). Samples were scored on a 0-4 scale (0 = none; 1 = few (<5 in focus); 2 = mild numbers (5-10); 3 = moderate numbers (11)(12)(13)(14)(15)(16)(17)(18)(19)(20); 4 = marked numbers (>20)) for numbers of mixed granulomas (ill-formed granulomas with a mixture of macrophages and lymphocytes), defined granulomas (well-defined with separation of macrophages, epithelioid, or multinucleated giant cells with lymphoid aggregates), perivascular lymphoid aggregates, peribronchiolar lymphoid aggregates, histocytes (macrophages), foamy macrophages, neutrophils, cholesterol clefts, and acid-fast bacteria. Scoring was performed by a pathologist who was blinded to the experimental condition of each sample.…”

“…For example, protection against aerosol challenge with Mtb conferred by intravenous BCG vaccination was linked to epigenetic reprogramming of bone marrow derived macrophages in mice [19]. Additionally, BCG vaccination was able to prevent immune pathology and bacterial dissemination independently of CD4 T cells in a mouse model of TB reactivation [20].…”

GABA potentiate the immunoregulatory effects of Lactobacillus brevis BGZLS10-17 via ATG5-dependent autophagy in vitro

“…In order to analyse the effect of L. brevis BGZLS10-17 supernatant on polyclonal proliferation of MLNC, the cells were labeled with carboxyfluorescein succinimidyl ester (CFSE, 1 µM, Thermo Fisher Scientific, Waltham, MA, USA) according to manufacturer's protocol, and then treated with Concanavalin A (2.5ug/ml, Sigma) either in the presence or absence of L. brevis BGZLS10-17 supernatants. The proliferation of CFSE-labeled MLNC was analyzed within live cells, as determined by simultaneous staining with propidium iodide (PI, Sigma, 10ug/ml) after the cultures, by flow cytometry according to Tomić et al 66 . The percentage of proliferation was calculated using the proliferation fit statistics in FCS Express 4 software (De Novo Software, Glendale, CA, USA).…”

Effect of dietary Lactobacilli mixture on Listeria monocytogenes infection and virulence property in broilers

“…PTGS2, also known Cox2, is an enzyme responsible for the synthesis of prostanoids. Studies have shown that PTGER2 has potential in producing anti-inflammatory cytokines including IL-10 in vivo ( Okla et al., 2019 , Tomić et al., 2019 ). IL-10/Cox2/PTGER2 could be influenced by Mycobacterium avium infection in dendritic cells and by Antrodia cinnamomea fermented product in chicken cells ( Kim et al., 2019 , Lee et al., 2019 ).…”