Sanne Hoeks

General Discussion 107 7 WINDOW OF OPPORTUNITY Anon-redundant priming period of the innate and adaptive immune systemafter birth sets the stage for immune homeostasis and host–microbial interaction. 22 This neonatal window of opportunity provides an explanation for the long-known fact that early environmental in uences can have lasting consequences. 23, 24 Of interest immune cell compositional changes after birth follow a stereotypic pattern of development in all children, despite their differences in both maturity and postnatal environmental conditions. 25 During this developmental trajectory, additional exposures and adaptive changes are required to eventually reach an adult-like immune state. For example, epidemiological studies show a strong correlation between early microbial exposure to allergens and a reduced risk of immune-mediated diseases later in life. 26, 27 In contrast, microbial dysbiosis during the first 100 days of life was associated with the development of asthma in a human birth cohort. 27 The fact that these first 100 days also represent a critical period in the development of B cells, natural killer cells (NK), and dendritic cells (DC), as these cell populations reach adult- like phenotypes during this period suggests that environmental influences imprinting on these cells in this period will have long-term consequences. T cell populations do not reach adult-like phenotypes during the first 100 days. 25 Thus such time window for T cells does either not exist or follows a different path than B cells, NK cells and DCs, requesting longer follow up studies. In chapter 4 is described that induced regulatory T cells are still highly present at the age of twelve months in comparison with adults. This presence of induced Tregs might partially explain the supposed window of opportunity to prevent immune-mediated diseases later in life. In a mouse model, it has been shown that exposure to Helicobacter pylori in early life protected the mice from asthma and other inflammatory conditions. 28, 29 Systemic depletion of Tregs abolished this protection from asthma whereas adoptive transfer of purified Treg cell populations from an infected donor to an uninfected recipient, was sufficient to restore protection. To investigate if Tregs are in humans also important to create a window of opportunity to induce immune tolerance, the phenotypical and functional classification of Tregs into three subpopulations have been used. 30 Human FOXP3 + CD4 + Tcells can be divided into resting Tregs (CD45RA + FOXP3 low ), activated Tregs (CD45RA-FOXP3 high ) and non-Tregs (CD4 + CD45RA - FOXP3 - ). Both resting and activated Tregs have suppressive functions and predominantly activated Tregs are present in the early neonatal period. 31 These Tregs have been activated in an antigen-specific manner to become subsequently highly suppressive in an antigen-nonspecific manner. 32, 33 Moreover Tregs, induced after exposure to S. Aureus, have the ability to convert neonatal conventional CD4 + T cells into Tregs via the PD-1/PD-L1 axis 34 and activation of neonatal v-omega-2 lymphocytes will lead to upregulation and prolonged expression of PD-1 that will effectively dampen proinflammatory responses after engagement to its ligand PD-L1. Additionally, an increase in the frequency and stability of Tregs was associated with more favorable clinical outcomes in children who underwent oral immunotherapy for peanut allergy. 35