Development of the human innate immune system throughout gestation

Almost four million neonates die of infectious and prematurity-related causes across the world annually. The innate immune system provides evolutionarily ancient first-line protection against most microbial pathogens. In contrast, the adaptive immune system is capable of developing an immunological memory that provides enhanced protection in vertebrates. A mechanistic understanding of the maturation of the human preterm neonatal immune system is lacking and this may limit our ability to develop more age-appropriate immunological therapies. In Chapter 1, I analyzed prototypic anti-microbial receptor responses in a clinically well-characterized cohort of premature infants to provide evidence that responses develop asynchronously and follow a developmental pattern that is independent of perinatal factors linked to the premature delivery. In Chapter 2, I dissected molecular rate-limiting steps along a major inflammatory pathway leading to the production of the interleukin-1β (IL-1β) cytokine, across development. The IL-1β cytokine is particularly important as its production serves to amplify innate immune responses. I show that premature neonates born early in the third trimester of gestation lack IL-1β responses due to a lack of activity in the caspase-1 enzyme. In the final chapter, I developed an efficient purification method to study the phenotype of neonatal invariant Natural Killer T (iNKT) cells. Using this method, I show that neonatal iNKT cells display heightened proliferative capacity compared to conventional T cells, consistent with an innate-like phenotype. Altogether, my work provides important insights into mechanisms and developmental characteristics of the fetus and early newborn immune system. This work forms the basis for future studies aimed at understanding how functional characteristics of the neonatal immune system can be therapeutically modulated to prevent neonatal infections.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat