UBC Theses and Dissertations
Neonatal lung group 2 innate lymphoid cells and their role in mediating type 2 immunity and allergen sensitization Steer, Catherine
Airway allergic diseases predominantly originate from early life exposure to allergens, but the mechanism behind this is unclear. Group 2 innate lymphoid cells (ILC2s) are critical for innate and adaptive immune responses to airway allergens in adult mice. Therefore, I hypothesized that ILC2s play an essential role in neonatal lung immunity. ILC2s quickly seed the mouse lung after birth and begin proliferating and producing IL-13 and IL-5 around postnatal day 10-14, inducing eosinophilia. Neonatal pups deficient for IL-33, an epithelial-derived alarmin that activates ILC2s, have fewer lung ILC2s and eosinophils at day 10 than wildtype (WT) pups. The amount of IL-33 in WT pups is high at day 10 and decreases after day 15, correlating with a contraction of ILC2s into adulthood. Thus, spontaneous release of IL-33 into neonatal lungs provokes activation of ILC2s and eosinophilia. Neonatal ILC2s are more responsive to intranasal (I.N) protease allergen papain than adult ILC2s and respond more intensely upon a secondary challenge in adulthood. Furthermore, ILC2s drive neonatal Th2-biased cell differentiation. I.N OVA antigen treatments into day 10 ILC2-deficient pups transplanted with OT-II adult CD4⁺ T cells results in fewer IL-4⁺IL-13⁺ CD4⁺ OT-II T cells in the lung-draining lymph node than in WT pups. Therefore, ILC2s play a role in neonatal sensitization to allergens leading to persistent allergic disease. The majority of neonatal ILC2s incorporate BrdU, and the BrdU-labeled neonatal ILC2s persist into adulthood, comprising almost 30% of adult lung ILC2s. To determine the effect of neonatal IL-33 exposure on ILC2 function, I.N IL-33 was given to IL-33-deficient (KO) and wildtype (WT) adult mice. While there was no difference in the number of lung ILC2s, there were fewer IL-5⁺IL-13⁺ ILC2s in IL-33KO than IL-33WT mice. I.N IL-33 into IL-33KO pups rescued the impaired response in adulthood. Microarray analysis showed cell-intrinsic differences between IL-33KO and IL-33WT ILC2s. Overall, weak activation by endogenous IL-33 of neonatal lung ILC2s may “train” ILC2s to respond strongly to allergen exposure later in life. These results place ILC2s as crucial components of neonatal lung immunity and should be taken into consideration when developing therapeutics for the prevention of allergic disease development.
Item Citations and Data
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