KIT Supports Small Intestinal Tuft Cell Hyperplasia

Abstract

A fundamental characteristic of multicellular biology is the continual turnover of specialized cells.These cells are characterized by their unique combination of transcribed RNA, proteins—such as membrane- bound signals and transcription factors—and spatial localization. Together, these properties generate unique cell types with specialized functions that interdependently maintain the multicellular organism. Historically, immunology focused on a diverse group of cells specialized for pathogen elimination. Early studies primarily investigated white blood cells such as T cells or macrophages1; however, there is now a broad appreciation that immune function depends on communication not only among these cells but also with non-hematopoietic cells. Central to this dialogue are secreted proteins, such as cytokines, chemokines, and growth factors, which collectively create an environment that supports the generation and activation of cells critical to an immune response. This coordinated signaling is exemplified in the immune response against a parasitic worm (helminth), where epithelial and lamina propria cells act in concert to initiate and sustain anti-helminth immunity. Soil-transmitted helminths (STHs) mature and reproduce in the small intestine, where the primary immune response is enacted. Helminths are detected by tuft cells, a rare specialized epithelial cell that produces interleukin (IL)-25 and cysteinyl leukotrienes (cysLTs). These mediators act synergistically to activate group 2 innate lymphoid cells (ILC2s) which in turn drive helminth clearance. Activated ILC2s secrete IL-4, -5, and - 13, characteristic cytokines of type 2 immunity. These interleukins coordinate hallmarks of the type 2 immune response such as increased muscle contraction, mucus secretion, and tuft cell hyperplasia. Among these, tuft cell hyperplasia is critical to the worm clearance, not just for the amplification of pathogen detection, but also for increased production of tuft cell-derived effector molecules. This expansion depends on IL-4/13 signaling within the small intestinal epithelium (SIE) and can increase tuft cell frequency up to 10-fold. Yet, despite the magnitude of this response, how IL-4/13 supports the expansion of tuft cells remains unclear. We show that tuft cells across all tissues express the receptor tyrosine kinase KIT, a growth factor known to support cell division, differentiation and survival in multiple cell types. We find that IL-4/13 is necessary and sufficient to upregulate KIT on small intestinal (SI) tuft cells. While epithelial KIT is dispensable for homeostatic turnover, KIT deletion from tuft cells during helminth infection reduces tuft cell hyperplasia and delays helminth clearance. Mechanistically, KIT signaling supports the generation of new tuft cells in SIE crypts. These findings identify a novel tuft cell-specific function for KIT in type 2 immune responses and highlight the coordinated efforts of cytokines and growth factors in establishing and maintaining immunity.