A Type 2 Innate Lymphoid Cell-Interleukin 9 Circuit Induces Paneth Cell Metaplasia and Small Intestinal Remodeling

ABSTRACT Paneth cell metaplasia (PCM) typically arises in the setting of pre-existing gastrointestinal (GI) diseases; however, the mechanistic pathway that induces metaplasia and whether PCM is initiated exclusively by disorders intrinsic to the GI tract has not been delineated. Herein, we describe the development of PCM in a murine model of inducible bcr/abl oncogene-driven chronic myelogenous leukemia (CML) in which metaplasia is causally and temporally linked to the development of leukemia. Mechanistically, CML induced a proinflammatory state within the GI tract that resulted in the production of epithelial-derived IL-33. Binding of IL-33 to ST2 led to the production of IL-9 by type 2 innate lymphoid cells (ILC2s) which was directly responsible for the induction of PCM in the colon and Paneth cell hyperplasia in the ileum. In addition, IL-9 directed remodeling of the small intestines characterized by goblet and tuft cell hyperplasia along with the expansion of mucosal mast cells. Thus, we identify that an extra intestinal disease can trigger an ILC2/IL-9 immune circuit which induces PCM and regulates epithelial cell fate decisions in the GI tract.