The developing fetal immune system is exquisitely sensitive to signals from the maternal environment. Maternal pre-pregnancy (pregravid) obesity has emerged as one of the most consequential regulators of fetal health. Data from clinical and animal model studies demonstrated increased susceptibility to microbial infection as well as a higher incidence of inflammatory disorders and auto-immune diseases with maternal obesity. This dichotomy is illustrated by splenocytes generating dampened inflammatory responses to LPS stimulation while gut resident immune cells generate exaggerated ones. Similarly, pregravid obesity resulted in lower expression of inflammatory genes in umbilical cord blood monocytes at rest, but following differentiation into macrophages, expression of inflammatory genes was significantly increased. These observations strongly suggest that pregravid obesity disrupts the development and maturation of the fetal immune system and differentially impacts circulating monocytes and tissue resident macrophages (TRMs). However, the molecular underpinnings of this dysregulation by maternal obesity remain poorly understood due to the difficulty of obtaining term fetal tissues and of controlling for multiple maternal variables that modulate fetal immunity. Thus, in this application, we will leverage the rhesus macaque model to interrogate multiple fetal compartments within the same subject to address this knowledge gap. Immune ontogeny occurs via 3 different waves starting with yolk sac, transitioning to fetal liver, and finally the bone marrow. TRMs are derived primarily from yolk sac and fetal liver while circulating monocytes are derived from bone marrow. We recently reported that pregravid obesity is associated with low grade inflammation that is further compounded by pregnancy. Thus, we postulate that exposure to low grade maternal inflammation leads to “training” of TRMs while heightened maternal inflammatory environment in late gestation leads to “tolerance” of bone marrow derived monocytes. Therefore, this application will test the central hypothesis that pregravid obesity results in differential rewiring of TRMs and circulating monocytes wherein TRMs are poised to generate a heightened inflammatory response while circulating monocytes display a stunted response. The novelty of this application lies in the systems biology approach integrating maternal clinical metadata with genomic and functional readouts obtained in multiple immune compartments in the same animal. Completion of the proposed experiments will reveal the molecular mechanisms that result in altered fetal macrophage and monocyte functions thus informing the potential development of early interventions.