Mechanisms of eosinophilia in Aspergillus fumigatus induced type 2 lung inflammation

Allergic airway inflammation affects millions of people worldwide thus constitutes a major health concern. Fungal sensitization often underlies eosinophilic allergic asthma, which is the predominant form of asthma in adolescents. So as the ubiquitous environmental mold Aspergillus fumigatus (Af), which can induce a hypersensitivity reaction characterized by an overshooting type 2 immunity, including eosinophilia. Despite Af-induced allergic conditions affect about 5 million people and treatment options are limited, the underlying immune response is insufficient understood. A murine Af sensitization model was applied in various genetically modified mice to better characterize mechanisms underlying eosinophilia in Af-induced lung inflammation This thesis demonstrate that innate type 2 lymphoid cells (ILC2s) cooperate with Th2 cells in enhancing eosinophilia in Af-induced lung inflammation. Surprisingly, the contribution of ILC2s to eosinophilia is independent of ILC2-derived IL-5. In contrast, only in male mice eosinophilia was driven by IL-4/IL-13 produced by ILC2s. This sex-difference could be partly explained by different eotaxin-2 induction in macrophages in male versus female mice. Moreover, the expansion of male ILC2s was driven by a crosstalk between type 2 conventional dendritic cells (cDC2s) and Th2 cells. Specifically, Th2 cells induced STAT6-dependent Il33 expression in dendritic cells and cDC2-intrinsic IL-33 was required for ILC2 expansion in male mice. Further it was elucidated that ILC2 promoting factors were induced in an IL-4+IL-33-dependent manner in cDC2s. Additionally, this IL-4+IL-33-driven changes seem promote a migratory phenotype in dendritic cells. In addition, the role of integrins for eosinophil recruitment to the Af-sensitized lung inflammation was investigated. Various knock-out approaches lead to the conclusion that single loss of integrin chains has only minor effects on eosinophil migration into lung tissue. Overall, this thesis contributed to enhanced understanding of the underlying type 2 immunity in Af-induced lung inflammation. Especially, a novel Th2-IL-33+ cDC2-ILC2-eosinophil axis appears to be important in male mice to elicit Af-induced allergic airway inflammation.