Tuft-Cell-Derived Leukotrienes Drive Rapid Anti-Helminth Immunity in the Small Intestine But Are Dispensable for Anti-Protist Immunity
This week we profile a recent publication in Immunity from the laboratory of
Dr. Jakob von Moltke (pictured, back row right) at the UW School of Medicine.
Can you provide a brief overview of your lab’s current research focus?
Our lab is broadly interested in understanding the branch of the immune system that evolved to combat parasitic helminths and that is often implicated in allergic diseases, known as type 2 immunity. While we have a good understanding of how the body detects and responds to the presence of bacteria, viruses, and fungi, our knowledge of the earliest sensing and signaling events that generate the anti-helminth type 2 response is comparatively lacking. In other words, how is it that the body knows when it is infected with a parasitic worm? A significant advance was made in 2016 with the discovery that a rare and largely neglected cell type, called the tuft cell, is responsible for detecting the presence of helminths in the small intestine. When a tuft cell senses a worm, it can signal to nearby immune cells to activate the type 2 response and promote worm expulsion. This exciting finding spurred many questions about tuft cell biology and the crosstalk that occurs with the immune system, which is the focus of the work in our lab.
What is the significance of the findings in this publication?
In this paper we asked: How do tuft cells regulate type 2 immune responses? Initial work identified the cytokine IL-25 as a key effector molecule that tuft cells secrete to initiate type 2 immunity. IL-25 is an important signal, but our preliminary data suggested it was not the whole story. Here, we found that tuft cells produce a second type of effector, called cysteinyl leukotrienes, that cooperate with IL-25 to amplify the type 2 response. Leukotrienes are inflammatory lipids that are best known for exacerbating asthma in the airways, but little is known about their role in the intestine. We found that tuft cells release leukotrienes upon sensing helminths in the lumen of the small intestine, and that this is an important signal for rapidly initiating the anti-helminth immune response. Accordingly, genetic deletion of leukotriene synthesis in tuft cells impaired the anti-helminth response and delayed worm clearance. This finding sheds light on how tuft cells are able to translate an initial sensing event into a robust immune response.
What are the next steps for this research?
An unexpected but exciting idea that emerged from this study is that tuft cell effector responses may be context-dependent. In addition to detecting parasitic helminths, tuft cells in the intestine can sense the presence of certain microorganisms, known as protists, that also trigger a type 2 immune response. Why tuft cells should respond to these protists remains a mystery as they are part of the commensal microbiome and do not seem to impair host fitness. We found that while tuft cells secrete leukotrienes to amplify type 2 immunity in the context of helminth sensing, this signal is completely dispensable in the context of protist sensing. We hypothesize that tuft cells may tailor their effector molecule output depending on the type of organism being sensed (ie. pathogen versus commensal), allowing for nuanced control over the immunological tone of the intestine. We hope to explore this idea in our future work.
This work was funded by:
Searle Scholars Fund, NIH New Innovator Award, Kenneth Rainin Foundation Synergy Award