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I Immune Sensing and Effector Functions of Small Intestinal Tuft Cells Immune sensing and effector functions of small intestinal tuft cells John W. McGinty A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2021 Reading Committee: Jakob von Moltke, Chair Andrew Oberst Martin Prlic Program Authorized to Offer Degree: Immunology i ©Copyright 2021 John W. McGinty ii University of Washington Abstract Immune sensing and effector functions of small intestinal tuft cells John W. McGinty Chair of the Supervisory Committee: Jakob von Moltke Department of Immunology Parasitic worm, or helminth, infection represents a significant global health issue, with roughly a quarter of the world’s population estimated to be infected at any given time. The branch of the immune system that evolved to defend against helminths is known as “type 2” immunity. While we have a good understanding of how the immune system detects and responds to viruses, bacteria, and fungi, the earliest sensing and signaling events that initiate the anti-helminth immune response remain poorly understood. Recently it was discovered that a rare and largely neglected cell type, called the tuft cell, specifically regulates type 2 immunity in the small intestine. Tuft cells secrete the cytokine IL-25, which activates group 2 innate lymphoid cells (ILC2s) in the underlying lamina propria to amplify the type 2 inflammatory response. Tuft cells were shown to respond to not only helminths, but also certain commensal protists. It remained unclear, however, how tuft cells detect helminths or protists in the intestinal lumen and what tuft cells do besides secrete IL-25. Looking upstream, we identified succinate as the first activating ligand for small intestinal tuft cells. We first sequenced tuft cells from various tissues, including the small iii intestine, to identify tissue-specific gene signatures. Using this data, we identified the succinate receptor, SUCNR1, as a candidate activating receptor that is highly expressed by intestinal tuft cells. Dietary supplementation with succinate activated a feedforward tuft-ILC2 response circuit, thereby inducing a robust type 2 immune response. We further demonstrated that succinate is a secreted metabolite of both helminths and Tritrichomonad protists. Succinate signaling through SUCNR1 was absolutely required for tuft cell sensing of protists, but unexpectedly, was dispensable for mounting an anti-helminth immune response. These findings reveal that innate type 2 immune responses can be activated by monitoring of microbial metabolism. Moreover, these data suggest that tuft cells utilize multiple activation pathways to sense luminal organisms, with the pathway(s) responsible for detecting helminths yet to be discovered. Upon sensing infection, tuft cells activate ILC2s, which subsequently drive increased tuft cell frequency. This feedforward circuit is essential for intestinal remodeling and helminth clearance. ILC2 activation requires tuft cell-derived IL-25, but whether additional signals regulate the feedforward circuit is unclear. Here, we found that tuft cells secrete cysteinyl leukotrienes (cysLTs) to rapidly activate type 2 immunity following chemosensing of helminth infection. CysLTs cooperated with IL-25 to activate ILC2s, and tuft cell-specific ablation of leukotriene synthesis attenuated type 2 immunity and delayed helminth clearance. Conversely, cysLTs were dispensable for the tuft cell response induced by intestinal protists. These findings identify a novel tuft cell effector function and suggest context-specific regulation of tuft-ILC2 circuits within the small intestine. Together, these findings advance our understanding of basic tuft cell biology, but more importantly, illuminate an unexpected complexity in how tuft cells discriminate between different environmental encounters. It appears that both the activating input signals and the iv resulting effector outputs of tuft cells are specifically tuned to the type of organism sensed. These observations could inform new approaches for the generation of novel, targeted therapies to most effectively help those afflicted by intestinal helminth infection, allergies, or other type 2- associated pathologies. v TABLE OF CONTENTS Copyright information ................................................................................................................. ii Abstract .....................................................................................................................................iii Table of contents ........................................................................................................................ vi List of figures............................................................................................................................ vii Acknowledgments ................................................................................................................... viii Chapter 1: Introduction............................................................................................................ 1 Helminth infection and type 2 immunity ..................................................................................... 2 Innate immune activation ............................................................................................................ 4 Tuft cells ..................................................................................................................................... 5 Dissertation objective and significance ........................................................................................ 8 Figures ...................................................................................................................................... 11 Chapter 2: Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit ...................................................................................................................................... 12 Introduction .............................................................................................................................. 13 Results ...................................................................................................................................... 16 Discussion ................................................................................................................................ 23 Material and Methods ............................................................................................................... 27 Acknowledgments .................................................................................................................... 42 Figures ...................................................................................................................................... 43 Supplemental Figures ................................................................................................................ 52 Chapter 3: Small intestinal tuft cells secrete cysteinyl leukotrienes to rapidly activate anti- helminth type 2 immunity ....................................................................................................... 53 Introduction .............................................................................................................................. 54 Results ...................................................................................................................................... 55 Discussion ................................................................................................................................ 68 Material and Methods ............................................................................................................... 74 Acknowledgments .................................................................................................................... 88 Figures ...................................................................................................................................... 89 Supplemental Figures .............................................................................................................. 103 Chapter 4: Summary and future directions ......................................................................... 110 Summary ................................................................................................................................ 111 Conclusions and future directions............................................................................................ 112 References ............................................................................................................................. 117 vi LIST OF FIGURES Chapter 1: Figure 1 .................................................................................................................................... 11 Chapter 2: Figure 1 .................................................................................................................................... 43 Figure 2 .................................................................................................................................... 45 Figure 3 .................................................................................................................................... 47 Figure 4 .................................................................................................................................... 49 Figure 5 ...................................................................................................................................
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