CD45 in Tuft Cells: A Gatekeeper of Intestinal Immunity
2Department of Systems Immunology, Weizmann Institute of Science
3Department of Life Sciences Core Facilities, Weizmann Institute of Science
4Department of Veterinary Resources, Weizmann Institute of Science
5Bioinformatics Unit, Weizmann Institute of Science
6Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev
7Division of Immunology, Immunity to Infection and Respiratory Medicine, The University of Manchester
The intestine is more than a digestive organ, it orchestrates a complex collaboration between intestinal epithelial cells, the microbiome, and immune cells to maintain balance and protect against pathogens. Disruption of this harmony can lead to diseases such as inflammatory bowel disease, colorectal cancer, and food allergies, severely affecting quality of life.
Tuft cells are a rare and specialized epithelial cell type in the intestine, known for their chemosensory capabilities and their critical role in type II immune responses. These cells initiate immunity against helminths by secreting IL-25, which drives IL-13 production by group 2 innate lymphoid cells (ILC2s). However, while their ability to coordinate immune responses is well recognized, the regulatory mechanisms that control tuft cell activity remain poorly understood. Unexpectedly, a study from our group discovered that tuft cells express CD45, previously thought to be exclusive to immune cells. This raised a critical question: what role does CD45 play in tuft cell function?
By analyzing our novel mouse model of tuft cell-specific CD45 knockout, we discovered that deleting CD45 enhanced type II immune responses during parasitic infections, leading to improved parasite clearance. This identifies CD45 as a gatekeeper that limits tuft cell-mediated immune activation. Mechanistic studies revealed a negative feedback loop: tuft cells stimulate IL-13 secretion by ILC2s to initiate immunity, while IL-13 upregulates CD45 expression on tuft cells, to dampen tuft cell activity and restore immune balance.
Our findings reveal a novel regulatory mechanism in tuft cell biology and provide new insights into epithelial-immune crosstalk. These discoveries have implications for understanding and treating type II immune-related diseases.