Our immune systems have evolved to protect us from a wide range of threats, including bacteria, viruses, allergens, and parasites. While research has revealed many of the ways the human body fights off these invaders, how exactly the immune system detects threats in the first place is one of the many mysteries immunologists are investigating.
Now, a new study from the Moltke Lab at UW Medicine describes how our body generates an enigmatic cell type, known as tuft cells, that detects parasitic worms and helps to mobilize an immune response. Worm infections, which are prevalent around the world, can be especially harmful for children who lack access to adequate sanitation.
The paper, published in the journal Science Immunology, adds to current understanding about how tuft cells differentiate from stem cells, identifies key molecular players in that process, and points to new possibilities for modeling tuft cells for further study.
Jakob von Moltke has always been interested in the immune system, in particular how different aspects of our complex defense networks work nonstop to detect foreign threats to our tissues and blood. As a graduate student at the University of California Berkeley, he studied how the immune system mobilizes against invading bacteria. In the course of that research, he gained an insight that would shape his career as an immunologist.
“While we were gaining a good understanding of how the immune system senses bacteria and viruses and fungi, we knew less about the sensing of parasitic worms and allergens,” says von Moltke, who is now an Associate Professor of Immunology at UW Medicine and a faculty member in the Institute for Stem Cell and Regenerative Medicine (ISCRM). “It’s a crucial question because the very first thing that has to happen in any immune response is detection.”
Because the human body faces a wide variety of threats – from microscopic bacteria to visible worms – it is no surprise that evolution has also produced a variety of ways to fight these threats, including structural defenses like skin, the rapid-response innate immune system, and an adaptive immune system that targets specific invaders and remembers those antigens for faster response to future attacks.
The Moltke Lab wants to know how a diverse set of agonists encompassing peanuts, worms, and other sources of irritation and misery induces a type 2 immune response that we often experience as sneezes and running noses. The researchers use gene-edited strains of mice to uncover the mysteries surrounding the early stages of that process.
While the lab is driven by curiosity about the underlying mechanisms of the immune response, the real-world implications are widespread and can be serious. Allergic reactions can range from mild to deadly. Meanwhile, more than 1.5 billion people worldwide suffer from parasitic intestinal worms. These infections can impair nutrition and growth and cause complications like anemia.
“When it comes to allergens and worms, we’re good at treating symptoms but not the underlying causes,” says von Moltke. “If we can understand how sensing happens we might be able to figure out what’s going on and intervene in a preventative way.”
The Moltke Lab has focused its attention on a distinctly shaped cell type known as tuft cells, named for their resemblance to brushes. Tuft cells, which have sensory machinery similar to taste buds, and are found in the trachea, stomach, urethra, and other tissues, are well known to be part of the lining of the intestines. Previous research by von Moltke and others first linked tuft cells to the detection of worm infection. But how this happens is less clear.
Tuft cells are rare in the intestine under normal circumstances but increase in quantity in response to worm infection when a particular protein (the cytokine IL-13) signals to progenitor stem cells. This leads to a rapid transformation in the make-up of the intestine that is possible because of the highly regenerative nature of the organ. Now, a new paper from the Moltke Lab, published in the journal Science Immunology, offers revealing information about the combination of molecules that regulate this immune response.
According to von Moltke, the study explores three intertwined questions. How are tuft cells derived from stem cells in the intestine? What causes more tuft cells to appear during infection? And what are the coordinating molecules – the transcription factors – that regulate this process? The research also builds on observations in the Moltke lab that different strains of gene-edited mice had different levels of tuft cells.
The first author of the paper is Marija Nadjsombati, PhD, a former graduate student in the Moltke Lab. The study, which von Moltke calls a whodunit, began when Nadjsombati realized that different strains of inbred mice had different levels of tuft cells, especially in their intestines. Nadjsombati then undertook a year-long backcrossing effort to generate mouse strains that would narrow down the genomic location of the gene(s) responsible for this difference. By comparing levels of tuft cells between the strains, Nadjsombati pinpointed a culprit gene, Pou2af2, located on chromosome nine.
Around that time, Xiaoli Wu and Chris Vakoc at Cold Spring Harbor Laboratory discovered that Pou2af2 encodes a protein that works with another prrotein, POU2F3 to convert stem cells into tuft cells. Here at UW Medicine, Nadjsombati discovered two different versions, or iosoforms, of the Pou2af2 RNA in the intestine. One isoform made a functional protein. The other, which was shorter, made a dysfunctional protein that could not interact with POU2F3. Mice with more of the functional isoform had more tuft cells.
In a twist, the mice with fewer tuft cells were not necessarily more susceptible to worm infection, in part because, according to the study, the number of tuft cells seems to shape only the innate immune response, not the ensuing adaptive immune response, which is responsible for fighting off parasites. Still, this innate immune response accounts for the sensing of certain unicellular protists in the small intestine and regulates the level of murine norovirus, which is a chronic infection in mice.
The paper also provides exciting opportunities for further study.
“The findings provide a better understanding of how tuft cells differentiate from stem cell,” says von Moltke. “The results also give us more information about the proteins involved in that differentiation and a new way of tuning that process. We can now look in greater detail at the mechanisms that are regulating the production of the functional or nonfunctional isoforms and how that might change during infection. We’ve also been looking for ways to engineer tuft cell lines and what we’ve learned opens a new entry point to do that.”
MSN was supported by a University of Washington Immunology Training Grant T32 AI106677 and by the UW Immunology Department Titus Fellowship. TEB was supported by the UW Immunology Fellowship, and DLJ was a UW Mary Gates scholar. Work at Columbia University was supported by NIH R35GM143051, Sloan Foundation Fellowship, Klingenstein-Simons Fellowship (all to AB). AB and JvM are Searle Scholars. JvM is a Burroughs Wellcome Investigator in the Pathogenesis of Infectious Disease. Work at Washington University was supported by R01AI139314 (MTB) and F31AI167499 (EAK). Work at the University of Washington was supported by NIH DP2OD024087 and R01AI167923.