Insights on the maturation steps of pulmonary immune responses in neonatal mice – a transcriptome-based study –

Early life events are critical for educating the immune system and setting an individual on a healthy trajectory. Both innate and adaptive immune responses in the neonate are immature at first, due to the necessity to tolerate maternal antigens during pregnancy to avoid inflammatory responses in the fetus and potential complications like premature birth or abortion1. As the neonate grows its immune system has to mature in a series of critical steps that will allow him to fight pathogens, to avoid exacerbated allergic reactions, and to limit the development of chronic inflammatory diseases. Notably, the first maturation steps of the pulmonary immune system are particularly critical in defining one’s susceptibility to lung diseases2. The development of the immune system starts in the yolk sac at embryonic day 8 (E7) in mice and week 3-4 in humans. Afterwards, it is taken over by the ventral wall of the aorta in the aorta-gonad mesonephros, and starting from week 5, hematopoiesis is initiated in the fetal liver. Extra embryonic hematopoiesis ceases around E12 in mice, week 10-12 in humans. The liver is the main hematopoietic site until birth in mice, and week 20-24 in humans. From the fetal liver, hematopoietic stem cells (HSCs) colonize the fetal thymus and spleen. At this stage, HSCs are expanding, however, they are not generated de novo. Just before birth, in mice, and during the second trimester, in humans, a small pool of HSCs colonizes the bone marrow. These bone marrow resident HSCs will be responsible for the maintenance of hematopoiesis throughout life3,4. At birth, the airways are exposed for the first time to the external environment and have to adapt quickly. Indeed, in utero the exposure to exogenous antigen is very limited. The embryo’s cellular immunity is poorly stimulated, and thus suboptimal in neonates, which have to rely mostly on innate responses5. In the neonate, both innate and adaptive immune responses are immature: (1) They have less CD4+ and CD8+ T cells, they can build strong Th2 responses but are weak at inducing Th1 responses as the threshold of Th1 stimulation is higher than in adults; (2) there are less dendritic cells, which are less mature and less inclined to promote Th1 responses; (3) regulatory T cells show lung- specific early expansion; (4) antibody production by B cells is impaired1,6-8. Overall, the immune system of a healthy neonate has to adapt to the external environment, and both the innate and adaptive responses have to adjust accordingly.There are still many unanswered questions on how the immune system develops in general, but also specifically in the lungs of neonates. The aim of this project is to discover the characteristics of these immune maturation steps in the lungs early in life, and to determine some of the mechanisms behind this process. More specifically the goals are: (1) to analyze mRNA sequencing data of hematopoietic cells from lungs of naïve mice during development (3, 8, 16 and 45 days of age) in order to identify the most interesting genes and pathways involved in immune maturation, and discover how they differ with age; and (2) to validate and characterize the most intriguing targets experimentally