Phenotypic Characterization of ILC2s in an EoE Mouse Model

Abstract

Abstract Loeys-Dietz Syndrome (LDS) is a genetic disorder caused by mutations in genes essential to TGFβ signaling including TGFBRI, which encodes a TGFβ receptor subunit. LDS patients exhibit a high prevalence of allergic disease. A mouse model of LDS Type I (TGFBR1M318R+/−) has been developed to further study this disease and its associated allergic conditions including eosinophilic esophagitis (EoE). EoE is characterized by the abnormal influx of eosinophils into esophageal tissue, basal cell hyperplasia, and smooth muscle dysfunction. The molecular mechanisms underlying this disease are not well understood, but Th2 cytokines are thought to play an essential role. TGFBR1M318R+/− mice spontaneously develop EoE with 100% penetrance, thereby providing an ideal model to study this allergic condition. Remarkably, TGFBR1M318R+/− mice continue to develop EoE in the absence of lymphocytes, suggesting that Th2 effector cells are not essential for driving EoE development. Further investigation has revealed increased numbers of type two innate lymphoid cells (ILC2s) in the esophagus of TGFBR1M318R+/− mice compared to wild type (WT) littermates. These cells are lineage negative, ST2+, GATA3+, and produce large amounts of IL-5 and IL-13, and to a lesser extent IL-4, following in vitro stimulation. The differences in ILC2 frequency between TGFBR1M318R+/− and WT mice appears around 10 days of age, while striking differences start to occur around 19 days, concurrently when ILC2 numbers peak in the normal esophagus. These large differences are sustained throughout the mouse’s lifespan, indicating that these cells may play a critical role in perpetuation of this disease. These findings support a novel role for ILC2s in driving EoE pathogenesis.