Sanne Hoeks

Summary 125 8 SUMMARY Fetal life and early infancy are recognized as a critical period to shape the immune system for life. Slowly the neonatal immune system changes its regulatory responses into effector responses. Genes, environmental factors and the interaction between both, the epigenome, will influence this maturation process and different developmental trajectories might be initiated leading to disease pathways. This concept has been recognized in the 1000 days campaign and the WHO’s Every Newborn Action Plan but pathophysiological mechanisms supporting this theory are mostly unidentified. In this thesis, it is pitched that immune homeostasis in early life is (partly) achieved by the unique increased ability of neonatal immunity to induce adaptive immune tolerance and that innate cells play an important role in driving this mechanism. Indeed, the predilection of neonatal naive CD4+ T cells to differentiate into FOXP3+ Tregs, in which PD-1/PD-L1 interactions play a role through a mechanism involving PKB signaling ( chapter 2 ), and the inability to differentiate into T H 17 cells, which is blocked at the level of RORC2 ( chapter 3 ), confirmed a profound programmed development of naïve T cells upon activation and their role in the development of immune tolerance in early life. Neonatal T cells develop the capacity to differentiate into T H 17 cells during the first 3 months and retained a propensity to become Treg cells until the age of at least 12 months ( chapter 4 ). However, IL-17, as well as high levels of IL-6 and TNFα are produced in vivo during severe neonatal infections, when strong pro-inflammatory stimuli are present. Thus, deficient innate and effector responses in neonates are partial and can be overcome once innate stimuli are strong enough ( chapter 5 ). System immunology, provided that it is standardized in use ( chapter 6 ), enables identification of divergent patterns in immune maturation related to long term health outcomes. It is crucial for long term health outcomes to protect and secure this programmed, age- dependent and stereotypic immune development. Therefore, unnecessary (longtime) antibiotic treatment should be avoided since this will disturb proper immune development by means of destruction of the composition of the microbiome and subsequently affects proper immune maturation. Development and clinical implementation of better diagnostic tools to identify or exclude neonatal sepsis are mandatory to secure future health outcomes.