Olfactory sensory neurons in the nose are supported by specialized epithelial cells, including microvillous cells (MVCs) that have a role in the mucosal immune response. Some MVCs express transient receptor potential cation channel subfamily member 5 (TRPM5), a protein that plays a role in taste transduction and the systems that sense temperature, smell, and mechanical forces.

TRPM5+ MVCs also express choline acetyltransferase (ChAT). TRPM5 and ChAT have been detected in tracheal, nasal respiratory, and intestinal tuft cells—taste receptor-expressing chemosensory epithelial cells present on mucosal surfaces that promote inflammation and epithelial remodeling. Tuft cell activation by parasites or metabolites derived from microbiota leads to activation of type 2 innate lymphoid cells (ILC2), then interleukin-13 (IL-13) driven type 2 inflammation and stem cell activation.

TRPM5+ MVCs have previously been considered distinct from tuft cells because of their morphology, low expression of taste receptors, and lack of close connections with sensory neurons.

Researchers at Brigham and Women’s Hospital now report in Science Immunology that TRPM5+ MVCs in the olfactory neuroepithelium not only are tuft cells but also have a role beyond triggering inflammation: they regulate olfactory stem cell proliferation.

The authors are Saltanat Ualiyeva, MD, a former fellow in the Vinik Center for Translational Immunology Research at the Brigham, Lora G. Bankova, MD, an associate physician in the Center and principal of the Bankova Lab, Adam L. Haber, PhD, principal researcher in the Haber Lab at Harvard T.H. Chan School of Public Health, and colleagues.

Methods

To determine how olfactory TRPM5+ MVCs relate to the rest of the chemosensory family and define their function in the olfactory mucosa, the researchers developed a comprehensive single cell RNA sequencing atlast of the olfactory and respiratory nasal mucosa and assessed the response to allergens in the olfactory and respiratory mucosa in vivo in mice that had specific genetic deletions of tuft cells, immune cells, and immune cell signaling.

The team also analyzed a dataset of human olfactory MVCs and compared them with murine nasal MVCs.

Results

The principal findings were:

• In both mice and humans, olfactory TRPM5+ MVCs are tuft cells; specifically, they share the core transcriptional profile of the chemosensory tuft cell family

• Compared with mucosal tuft cells that initiate the ILC2–IL-13 pro-inflammatory loop of epithelial stem cell activation, olfactory TRPM5+ MVCs have a more limited role as immune regulators: they direct olfactory stem cell proliferation independently of innate lymphocytes and inflammatory cascades

The study thus identifies a direct link between allergen sensing by tuft cells and activation of a reserve neural stem cell population.