Development of the neonatal immune system in the premature infant

Newborns lack educated adaptive immunity and therefore rely on innate immune defenses to protect themselves from infections. Premature babies are at high risk of severe infections due to the immaturity of their immune system. Umbilical cord blood is readily accessible to study the premature neonate’s immune system, but it does not capture important maturation events that may occur during the neonatal period. The overall goal of my PhD was to investigate the immune system of premature infants during the neonatal period. In chapter 2, I examined the whole blood response to immune stimulation of two prototypic Toll-like receptors: TLR4 and TLR7/8, in preterm infants aged 1-42 days in the neonatal intensive care unit. I identified major functional deficits in pro-inflammatory cytokine levels compared to term cord blood, which were not due to a lack of immune cells. These findings support previous observations made from preterm cord blood studies. To the best of our knowledge, we were the first at the time to study functional TLR responses during this critical development period. In chapter 3, I used RNA-sequencing methods to investigate how these responses are developmentally regulated. Using deconvolution algorithms, I found that preterm cord blood is distinct from preterm postnatal blood and term cord blood, with a gradual transition from an immature immune system enriched in hematopoietic stem cells, myeloid and erythroid progenitor cells, to a more mature immune cell composition in term cord blood. I also provide the first data directly linking immaturity of the preterm immune system to the risk of sepsis. In chapter 4, I examined innate-like characteristics of naïve CD4 T cells in term cord blood, as a means whereby newborns may compensate for a lack of adaptive memory immune cells. I demonstrate that activation of the antigen presenting cell is important to enhance innate-like IL-8 production in naïve CD4 T cells. The work within this thesis further characterized the immune function of newborns across the gestational age spectrum, providing novel insights into their immune development and factors underlying the high susceptibility of premature infants to infection.Medicine, Faculty ofExperimental Medicine, Division ofMedicine, Department ofGraduat