Sanne Hoeks

Chapter 7 104 THE NEONATAL IMMUNE SYSTEM: A BALANCING ACT Increased adaptive immune tolerance in early life: programmed naive T cells and a role for PD-1/PD-L1 T cell-APC interactions To secure the developmental trajectory of the immune system, the road to adult immunological wellness, and to prevent long term risk of immune-mediated diseases, knowledge of neonatal immune development and especially the drivers of this immune development like nutritional components, microbes and host-cell interactions is cardinal. In this thesis, it is pitched that immune homeostasis in early life is (partly) achieved by the 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 naive CD4 + T cells to differentiate into FOXP3 + Tregs described in chapter 2 , confirmed a profound programmed development of naïve T cells upon activation. Besides a clear inborn default of naïve T cells to differentiate into Tregs, cross experiments illustrated that neonatal APC were more potent in driving Treg development due to increased expression levels of PD-L1. The interaction between the negative signaling receptor PD-1 on the T cell and PD-L1 on the APC is one of the several physiological feedback control mechanisms which serve to block T cell proliferation under chronic antigenic stimulation 1 , which starts immediately after birth on the skin, mucosa in the gastrointestinal tract and in the airways. Of interest, PD-1/PD-L1 interactions also play a role in tumor immunology and PD-1/PD-L1 inhibitors can be very effective, unlocking anti-tumor activity in tumor-specific T cells and macrophages. We now showed that PD-1/PD-L1 interactions also play a role in Treg induction and thus the development of immune tolerance in early life. Differentiation into FOXP3 Treg cells involves reduced PKB signaling PD-1 signaling in CB T cells facilitated their differentiation into induced functional FOXP3 + Treg cells through a mechanism involving reduced PKB signaling ( chapter 2 ). CB T cells required approximately 10-fold more TCR triggering than APB T cells before an increase in PKB phosphorylation was observed. Our date fit those of Huygens and Kollmann who showed that newborn effector T cells are limited by a more rapid onset of functional exhaustion compared to adult T cells. 2, 3 Expression of PD-1 by T cells is reported to be one of the hallmarks of exhaustion. 1, 4 Therefore it is not surprising that PD-1 on neonatal T cells has been proposed as a potential target to reverse neonatal T cell exhaustion and to initiate a more robust inflammatory response. 1, 4 Note however, that our data showing a crucial role for PD-1 in FOXP3 induction indicate that such therapy may interfere with neonatal tolerance and therefore may have detrimental side effects. T H 17 differentiation in CB is blocked at the level of the lineage transcription factor, RORC2. In chapter 3 , we hypothesized that the propensity of Treg cell induction in cord blood (CB) could be explained by a regulatory mechanism that inhibits T H 17 cell development. Treg and T H 17 cells have a reciprocal developmental pathway. They also play a reciprocal role in