Project Summary Over one quarter of extremely preterm infants die during the first months of life. Dysregulation of inflammation and aberrant host-microbial interactions play a central role in the development of the three most common contributors to neonatal mortality: bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and sepsis. In recent years, a novel paradigm has emerged that identifies the important role of myeloid-derived suppressor cells (MDSC) in the regulation of newborn inflammation. We hypothesize that transitory expansion of MDSC may be one the mechanisms that provides protection against infectious mucosal injury in newborns. We found that MDSC observed in newborn mice have much higher antibacterial and anti-fungal activity than neutrophils and monocytes in adults. This may provide a crucial, additional layer of protection in newborns. Our data indicate that the appearance of MDSC is closely connected to gestational maturity, with significantly lower expression observed in very premature babies who are at high risk for BPD, NEC, and sepsis. The overall goal of this study is to determine the mechanism and clinical significance of MDSC accumulation in preterm newborns and characterize the therapeutic potential of these cells in the prevention and recovery from BPD, NEC, and sepsis. To achieve this goal we propose three specific aims. Specific aim 1: To characterize the natural history and identify the mechanisms regulating transitory accumulation of MDSC during first weeks of life. Specific aim 2: To determine the significance of MDSC in the development of bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and sepsis in very low birth weight infants. Specific aim 3: To identify the potential therapeutic effect of MDSC to control inflammation in newborn mice.