Development of intestinal immunity Spilling the guts on T cell maturation and inflammation in the early-life intestine

Early life is characterized by a sequence of unique immunological challenges. The fetal immune system performs a balancing act between protection from infections and prevention of harmful immune responses that could result in premature termination of the pregnancy. Upon birth, the newborn infant faces the unique challenge of transitioning from a relatively sterile womb to an antigen‐rich world. After birth, the immune system has to rapidly evolve with each antigenic challenge, leaving young infants particularly vulnerable to infectious disease. This thesis demonstrates that in the intestine, immune development is initiated at the end of the first trimester of human fetal gestation and that it changes with age, adapting to the unique challenges presented by each stage of early life. Fetal intestinal immunity is fronted by tissue-resident tumor-necrosis-factor-α-producing T helper (Th) 1 cells that guide intestinal development in utero. However, the predominance of these pro-inflammatory cells in the gut during gestation predisposes the early-life intestine to develop exacerbated inflammatory responses, such as necrotizing enterocolitis, upon premature exposure to foreign microorganisms due to (extremely) premature birth. The intestinal immune system in infants after birth is characterized by specialized natural killer cells, dampened cytotoxic T cell responses and a heterogeneous population of T helper cells including T regulatory, Th2, Th17 and especially follicular Th cells. The rapidly developing immune system after birth leaves infants particularly vulnerable to gastrointestinal infections. However, the identification of large numbers of functional follicular Th cells shortly after birth suggests a promising avenue for early-life vaccine design.