PROJECT SUMMARY/ABSTRACT Premature birth is a leading cause of infant mortality in the United States, and lung immaturity in these babies is a major cause. As the organ of gas exchange, efficient lung function is critical for the survival of the newborn. At birth, premature lungs are in the saccular developmental stage, an immature state compared to the mature adult lungs. These immature lungs are first exposed to airborne material and microbes at birth, and thus need to be poised for defense. Dendritic cells (DC) play a key role in this barrier defense and initiating immunity, however, our understanding of DCs in these immature lungs is limited. My investigations into newborn lungs have revealed previously unknown phenotypic heterogeneity within the early-life DC compartment. Furthermore, these newborn lung DC subsets are transcriptionally distinct from their counterparts in later neonatal stages. Together our data support the idea that the DC compartment in saccular stage lungs is phenotypically and functionally distinct from the adult. These observations lead to our hypothesize that newborn lungs contain phenotypically and functionally heterogeneous stage-specific lung DCs. This hypothesis will be addressed through the following specific aims: Aim1: interrogate the ontogeny of saccular stage lung DCs, and Aim 2: Determine the functions of saccular stage DCs. Both of these aims will be performed in comparison to other lung development stages, including mature lungs. These aims will elucidate the saccular stage DC compartment in terms of ontogeny and function, and will reveal its significance in neonatal lung inflammation. The proposed research will be the first comprehensive analysis of the lung DC compartment at birth and its role in inflammation.