Preterm birth skews the developmental trajectory of myeloid-derived suppressor cells in the first 48 hours of life: single-cell transcriptomics and inferred intercellular communication

Prematurity is a leading cause of neonatal and childhood mortality, with infections driving early deaths. Innate immunity provides frontline defense after birth and is shaped in part by myeloid-derived suppressor cells (MDSCs). The role of MDSCs in regulation of neonatal immunity, especially in the context of prematurity, remains elusive. We sought to understand the transcriptional landscape of neonatal immune myeloid regulators, specifically differences between preterm and full-term neonates. Insight into specific cellular networks could help understand how to skew preterm MDSCs’ development towards classical immunotolerant and anti-microbial mechanisms. This cross-sectional study used single-cell RNA sequencing to characterize the neonatal MDSC transcriptional landscape, developmental trajectories, and predicted signaling networks within 48 h after birth. Peripheral blood mononuclear cells were isolated from 7 preterm neonates (< 36 weeks gestational age), 6 full-term neonates (> 37 weeks), and 6 healthy adult (21–45 years old, control). Primary exposure was premature birth and neonatal intensive care hospitalization from a single-center, academic tertiary care hospital between 2023 – 2024. Among ~ 339,000 cells, preterm neonates exhibited enrichment of polymorphonuclear MDSCs (10.6% ± 5.3%) vs full-term (2.6% ± 1.3%) and adults (0.4% ± 1.3%). Trajectory analysis identified a prematurity-associated differentiation branch characterized by inflammatory signaling, mitochondrial stress, and heightened protein-translation programs, distinct from a conserved, tolerogenic MDSC trajectory present across ages. Cell-communication modeling showed intensified outgoing and incoming signaling via ADGRE, RESISTIN, TGF-β, ANNEXIN, and ICAM networks. Antigen presentation signatures suggested preserved MHC-I output and diminished MHC-II interactions in neonates, with increased MHC-I input to preterm polymorphonuclear MDSCs. Prematurity is associated with early divergence of MDSC maturation toward an inflammatory and metabolically stressed PMN-MDSC state with altered immune communication. These findings identify cellular mechanisms that may contribute to the heightened tissue damage and infection susceptibility of preterm neonates and highlight MDSC signaling as a potential target for early-life immunomodulatory interventions.