Sanne Hoeks

Chapter 7 106 TRAINED IMMUNITY As illustrated by our data on APC-T-cell interactions in chapter 2 and 3 , innate cells undergo important developmental changes during the first weeks-months postnatally. These developmental changes in expression of costimulatory factors like PD-L1 and changes in PKB signaling clearly determine the quality and quantity of T effector responses postnatally. Regarding the immune developmental steps postnatally, the phenomenon “trained immunity” seems applicable. Trained immunity is explaining that innate immune cells are able to memorize encounters with pathogens or stimuli and respond in a sensitized and nonspecific manner to restimulation. 11-14 For example, neonates given a bacillus Calmette-Guérin (BCG) vaccination which has toll like receptor 2 (TLR2), TLR4, TLR8 and TLR9 agonist activity, experienced a non- specific reduction in neonatal mortality over neonates who did not receive BCG. 15-18 Thus trained immunity boosts the frontline of host defense in neonates and these adaptations of APC to environmental requests will also influence their interaction with T cells. The enhanced immune response that develops upon reencounter with the antigen is associated with a profound change in the intracellular metabolism and regulated by epigenetic changes at the level of histone modifications. 12, 19, 20 The capacity for trained immunity to confer broad immunological protection has sparked speculation that this process can be exploited to improve vaccination strategies. 21 On the other side, unresolved inflammation drives and exacerbates structural changes of tissue. For example in monocytes, promotors of pro-inflammatory genes such as IL- 6, IL-8 and TNFα, acquire regulatory changes in histone methylation when exposed to training stimuli that, upon rechallenge, support enhanced gene activation and cytokine production. 21 The deleterious effects of trained immunity on the developing tissue are not restricted to cytokine production, but also include the epigenetic reprogramming of genes encoding for functional proteins, scavenger receptors involved in host defense and chemokines responsible for recruiting circulating immune cells. 21 In conclusion, the interaction between cellular players and the concept of trained immunity illustrates the capacity of the neonatal immune system to respond to environmental inputs in a flexible and adjustable manner. The concept definitely needs further exploitation to enhance immune defense against pathogens and vaccination strategies in neonates without damaging the developing tissues.