Transitory presence of myeloid-derived suppressor cells in neonates is critical for control of inflammation

Abstract

Myeloid-derived suppressor cells (MDSC) are pathologically activated and relatively immature myeloid cells, which are implicated in the immune regulation of many pathologic conditions1,2. Phenotypically and morphologically MDSC are similar to neutrophils (PMN-MDSC) and monocytes (M-MDSC). However, they have potent suppressive activity, a distinct gene expression profile, and biochemical characteristics3. None or very few MDSC are observed in steady state physiological conditions. Therefore, until recently, accumulation of MDSC was considered as a consequence of pathological process or pregnancy. Here, we report that MDSC with a potent ability to suppress T cells are present during the first weeks of life in mice and humans. MDSC suppressive activity was triggered by lactoferrin and mediated by nitric oxide, PGE2, and S100A9/A8 proteins. Newborn MDSC had a transcriptome similar to that of tumor MDSC, but with a strong up-regulation of an antimicrobial gene network and had potent antibacterial activity. MDSC played a critical role in control of experimental necrotizing enterocolitis (NEC) in newborn mice. MDSC in infants with very low-weight, which are prone to the development of NEC, had lower MDSC levels and suppressive activity than infants with normal weight. Thus, the transitory presence of MDSC may be critical for regulation of inflammation in newborns.

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

“…As such, while the MDSCs may internalize dead bacteria, they do not serve as a permissive environment for intracellular growth and protection from the effects of gentamicin. Therefore, our findings presented here are not in conflict with those of He et al . This group reported a slightly greater than twofold reduction in bacterial viability when E. coli was incubated directly with monocytic or granulocytic MDSCs, although the detailed methods were not provided .…”

“…Approaches to reduce the abundance of MDSCs directly may prove challenging and could be deleterious. MDSC abundance early in life has been suggested to be valuable for limiting inflammation in the newborn during initial colonization by commensal bacteria . However, identification of the full range of effector mechanisms that MDSCs use to regulate immunity may offer the potential to antagonize specific immune compromising activities without eliminating the cells.…”

Neutrophil Diversity in Health and Disease

“…Humans Recent studies have reported that immunosuppressive neutrophil populations, that display a heterogeneous phenotype of mature activated and immature cells, might play a role in fetomaternal immune tolerance and in preventing pathological conditions in neonates [50][51][52][53][54]. These immunosuppressive low-density neutrophils (LDNs), also known as polymorphonuclear myeloidderived suppressor cells (PMN-MDSCs) (Boxes 1 and 2), have been described in the blood of neonates [50,53,54], as well as in the blood [54], placenta [51], and breast milk [52] of pregnant women. They can efficiently suppress CD4 + and CD8 + T cell proliferation in vitro, mostly via reactive oxygen species (ROS) production [54].…”

Dissecting the defects in the neonatal CD8+ T-cell response

“…In addition to increased frequency of Tregs, neonates have an increased frequency of myeloid‐derived suppressor cells (MDSCs) within peripheral blood, which decreases over the first months of life . The suppressive abilities of neonatal MDSCs are mediated through nitric oxide, Prostoglandin E2, and S100A9/S100A8 proteins and are induced through lactoferrin . The increased frequency of MDSCs within neonates may be a mechanism to promote tolerance to microbial colonization .…”