Sanne Hoeks

General Discussion 109 7 LAYERED IMMUNITY AND IMMUNE COMPUTATION This vigilant immune system is mandatory when the neonatal period is complicated by an invasive infection and demands adaptation of neonatal immune responses. Neither a single marker nor a binary distinction in the immune response (innate vs adaptive responses; suppressors vs effectors; T H 1 vs T H 2; etc) reflects this adaptation. Therefore, two theoretical concepts about immune development in mammals are proposed: layered immunity and immune computation. Layered immunity Layered immunity was originally developed to explain immune cell ontogeny but it may provide a broader framework to understand the maturation of the innate and adaptive immune system as a whole. 36, 37 For example, a fetal immune response to exogenous antigens is actively suppressed by antigen-specific Tregs, and these fetal Tregs are derived from a fetal-specific lineage of T cells, a lineage generated by an HSPC that is distinct from that found in adults. Fetal and adult T cells derive from hematopoietic stem cells that originate in different tissues (respectively, liver and bone marrow) and have distinct properties: Fetally derived cells exhibit higher proliferative capacity and are more prone to a tolerogenic response. Also, the induction of peripheral tolerance to self-antigens may have to precede the tolerance to microbial and dietary antigens at mucosal sites. 38-43 This would suggest that the immune system is comprised of distinct waves, present at different time points in life. 44 Clearly, developmental mechanisms contribute significantly to the initial adaptation to microbial exposure. Prematurity might reduce the ability to undergo innate immune tolerization and reprogramming, therefore increasing the risk to develop necrotizing enterocolitis (NEC), a condition in which incidence and severity rises with lower gestational age at birth. Consistent with this theory, an enhanced innate immune receptor expression and susceptibility to microbial ligands have been demonstrated in mouse fetal intestinal epithelium. 45 The immune profiles for babies born at earlier gestations change more dramatically over a similar time period to those born at later gestations, which suggests that extremely preterm babies are capable of rapid progression to ‘catch up’ immune function. 46 Moreover, the layered development of the immune system is evolutionarily driven and follows a cost–benefit principle. The maintenance of an elaborate immune system may come at a price and may have to be adapted to the availability of energy resources that at this time-point might rather be dedicated to growth and development. 43 It is undefined which events are involved in progression to the next phase of immune development. It is proposed that the immune system is equipped with an experience-based machine learning strategy which is analogous to that deployed by supervised machine- learning algorithms. 47 However, this theory is still hypothetical and future experiments are necessary to clarify proof of concept.