Tuft cells are a specialized type of cell named for their distinctive brush-like appearance. They are characterized by a prominent “tuft” of long, thick microvilli that project from their apical surface into the surrounding lumen or space. Tuft cells function as sentinels, sensing external stimuli and initiating responses within the body.
Where Tuft Cells Reside
Tuft cells are widely distributed throughout the body’s epithelial linings, especially in organs interacting with the external environment. They are found in the gastrointestinal tract, including the stomach, small intestine, and colon, where they monitor luminal contents.
Beyond the digestive system, tuft cells also inhabit the respiratory tract, from the nose to the alveoli in the lungs, where they are sometimes called brush cells. Their presence extends to glandular structures such as salivary glands, bile ducts, and the pancreatic duct. Tuft cells are also identified in the thymus and urethra.
How Tuft Cells Sense
Tuft cells possess chemosensory capabilities, allowing them to detect specific chemical signals akin to taste buds in the mouth. They express various chemosensory proteins, including TRPM5 and alpha-gustducin, which are typically associated with the transduction of bitter and umami tastes. This molecular machinery enables them to act as “taste buds” for internal organs, monitoring the luminal environment for specific molecules.
Tuft cells can detect diverse stimuli, such as succinate, a metabolite produced by parasites like helminths and protozoa. They achieve this through specific receptors like succinate receptor 1 (SUCNR1) on their surface. The binding of these ligands to their receptors triggers intracellular signaling cascades, often involving G-protein-coupled receptor (GPCR) pathways, similar to those found in taste cells.
These signaling pathways involve components like phospholipase C beta 2 (PLCĪ²2) and the transient receptor potential ion channel TRPM5. Activation of these pathways leads to the release of effector molecules, allowing tuft cells to relay information to adjacent epithelial cells, immune cells, or nerve fibers. This sensing mechanism allows tuft cells to detect various irritants and pathogens, including allergens and bacteria.
Tuft Cells and Immunity
Tuft cells play a significant role in the immune system, particularly in initiating Type 2 immune responses. When these cells detect specific stimuli, such as parasitic worms or certain allergens, they release a range of signaling molecules. These include cytokines like interleukin-25 (IL-25), interleukin-33 (IL-33), and thymic stromal lymphopoietin (TSLP), as well as eicosanoids such as cysteinyl leukotrienes and prostaglandin D2 (PGD2), and the neurotransmitter acetylcholine.
Interleukin-25 is a tuft cell lineage-defining cytokine, with tuft cells being the sole producers of IL-25. These secreted molecules act as alarmins, activating other immune cells. For instance, IL-25 and IL-33 stimulate group 2 innate lymphoid cells (ILC2s), which in turn produce additional Type 2 cytokines like IL-5 and IL-13.
This signaling cascade contributes to protective responses aimed at expelling pathogens, such as the “weep and sweep” responses in the intestine that help clear helminths. The release of these mediators can also contribute to allergic reactions by promoting Type 2 inflammation, characterized by features like eosinophilia and mucus hypersecretion. The synergy between molecules like cysteinyl leukotrienes and IL-25 demonstrates the role of tuft cells in shaping the immune landscape of mucosal tissues.
Tuft Cells and Health Conditions
Tuft cells are involved in various health conditions, stemming from their roles in sensing and immunity. Their ability to detect parasitic infections, such as those caused by helminths, leads to a Type 2 immune response that aids in expelling these invaders. The number of tuft cells can increase during parasitic infestations, reflecting their active participation in host defense.
Beyond infections, tuft cells contribute to allergic diseases like asthma and food allergies. Their release of cytokines such as IL-25 and TSLP, and eicosanoids like cysteinyl leukotrienes, can drive the Type 2 inflammatory responses characteristic of these conditions. Elevated levels of these mediators are associated with allergic asthma and disease severity.
Research also links tuft cells to certain cancers and inflammatory bowel diseases (IBD). Dysregulation of tuft cells has been implicated in gastrointestinal disorders, including colorectal cancer, where tuft cell genes are highly expressed. In models of radiation injury and IBD, tuft cells have shown a pro-regenerative capacity, suggesting involvement in tissue repair and disease progression.