Neonatal MDSCs compromise macrophage control of encapsulated bacteria

Abstract

Abstract Limitations in innate and adaptive immunity have been described early in life that contribute to susceptibility to microbial infection. Interleukin (IL)-27 is a heterodimeric cytokine produced primarily by antigen presenting cells and suppressive toward a variety of immune cell types. We have shown in humans and mice that neonatal macrophages express IL-27 at an elevated level as compared with adults. In mice this was shown to be maintained through infancy. Using the mouse as a model system, we have recently shown that myeloid-derived suppressor cells (MDSCs) are more abundant in the spleens of neonatal and infant mice and contribute to elevated IL-27 levels in young mice. Functional studies demonstrate that these MDSCs express active nitric oxide synthase, phagocytic oxidase complex, and arginase-1. Few studies have investigated the influence of MDSCs on innate immune function during bacterial infection. Streptococcus agalactiae and Escherichia coli are significant concerns for newborns as common causes of sepsis. We investigated the influence of neonatal and infant MDSCs cultured with infected macrophages and show impaired macrophage control of S. agalactiae and E. coli. Furthermore, the suppressive effect of MDSCs on macrophage function requires IL-27. Inclusion of a soluble receptor to neutralize IL-27 promotes increased control of bacterial growth. Our data suggests that the effect of MDSCs and IL-27 involves a direct influence on macrophage effector functions since inflammatory cytokines such as TNF and IL-6 are not significantly altered by the presence of MDSCs. Taken together these results suggest that the increased abundance of MDSCs and IL-27 production may contribute to some of the limitations in early life immunity.