Murine myeloid‐derived suppressor cells are a source of elevated levels of interleukin‐27 in early life and compromise control of bacterial infection

Abstract

Microbial infections early in life remain a major cause of infant mortality worldwide. This is consistent with immune deficiencies in this population. Interleukin (IL)‐27 is suppressive toward a variety of immune cell types, and we have shown that the production of IL‐27 is elevated in humans and mice early in life. We hypothesize that elevated levels of IL‐27 oppose protective responses to infection during the neonatal period. In this study, we extended previous findings in neonatal mice to identify a population of IL‐27 producers that express Gr‐1 and were further identified as myeloid‐derived suppressor cells (MDSCs) based on the expression of surface markers and functional studies. In neonates, MDSCs are more abundant and contribute to the elevated pool of IL‐27 in this population. Although the ability of MDSCs to regulate T lymphocyte activation has been well‐studied, sparingly few studies have investigated the influence of MDSCs on innate immune function during bacterial infection. We demonstrate that macrophages are impaired in their ability to control growth of Escherichia coli when cocultured with MDSCs. This bacterium is a significant concern for neonates as a common cause of bacterial sepsis and meningitis. The suppressive effect of MDSCs on macrophage function is mediated by IL‐27; inclusion of a reagent to neutralize IL‐27 promotes improved control of bacterial growth. Taken together, these results suggest that the increased abundance of MDSCs may contribute to early life susceptibility to infection and further highlight production of IL‐27 as a novel MDSC mechanism to suppress immunity.

Elevated levels of interleukin-27 in early life compromise protective immunity during neonatal sepsis

“…Neonates exhibit elevated levels of IL-27 in the spleen and blood at resting state relative to adults (11, 12). To determine if IL-27 levels continue to rise during infection and how the cytokine may impact the host response, we established a murine model of neonatal sepsis.…”

“…We have previously shown that MDSCs and macrophages are the dominant cellular sources of IL-27 in neonatal mice in the absence of infection (11, 12). To determine cell types that contribute to the rising IL-27 levels during infection, we profiled cells in the blood and spleens by immunofluorescent labeling and flow cytometry.…”

“…Fewer numbers of immune cells have been found in circulation with defects reported in microbial elimination processes, antigen presentation, T cell priming, and T cell receptor repertoires (7-9). In addition, increased amounts of cytokines such as IL-10, IL-23, and IL-27 are present, further supporting an anti-inflammatory bias (10-12). This is consistent with reduced production of tumor necrosis factor (TNF)-α from neonatal cells in response to TLR ligands compared with those from adults (13).…”

“…The contents were strained through a 40-um nylon strainer to remove residual tendon and ligament tissue, and erythrocytes were lysed using 0.2% sodium chloride and neutralized in 1.6% sodium chloride. Following a wash with phosphate-buffered saline (PBS), bone marrow cells were differentiated in DMEM that contained 2 mM glutamine, 25 mM HEPES, 10% FCS, and 10% L-cell-conditioned medium for 5-7 days at 37°C with 5% CO 2 as described previously (12). MDSCs were cultured in DMEM that contained 2 mM glutamine, 25 mM HEPES, and 10% FCS.…”

“…In macrophages, inflammatory cytokine production, inflammatory cytokine receptor expression and signaling, intracellular trafficking to lysosomes, and lysosomal acidification are negatively regulated by IL-27 (22, 26-31). This regulatory activity has been shown to compromise control of M. tuberculosis, S. aureus, P. aeruginosa , and E. coli (12, 26, 27, 30, 31). On the other side of the spectrum, IL-27 induces an inflammatory profile in monocytes (32).…”