In a study published in Immunity on March 22 2022, the research groups of Prof. FAN Zusen from the Institute of Biophysics of the Chinese Academy of Sciences reported that Tuft-2 cells participate in antimicrobial immunity via sensing bacterial metabolite N-C11-G (N-undecanoylglycine)

The mammalian gut is not only an organ of nutrient absorption, but also one of the largest peripheral immune organs. Intestinal epithelial cells (IECs) constitute barrier surfaces that separate mammalian hosts from the external environment. There are five main cell lineages in the intestinal epithelium: Enterocytes, Paneth, Goblet, Tuft, Enteroendocrine. All of the epithelium are derived from Lgr5+ intestinal stem cells.

IECs sense contents of intestinal lumen, including nutrients, microbiota, and metabolites, crosstalking with immune cells in the lamina propria to orchestrate intestinal homeostasis and immunity. Fan's group previously discovered NKB (Immunity, 2016) and ILCreg (Cell, 2017) as new subpopulations of innate lymphoid cells and defined their functions on anti-infection and resolution of inflammation.

Tuft cells were defined by their morphologic characteristics over 50 years ago. However, the function of Tuft cells remained unclear for decades. Recently, Tuft cells were considered as chemical sensors and a major constituent of the small intestinal response to parasitic helminths and protists. However, it remains insufficiently clear whether Tuft cells participate in bacterial eradication.

Through single-cell RNA sequencing (scRNA-seq), intestinal Tuft cells are clustered into two separate subpopulations, Tuft-1 and Tuft-2 subsets. Tuft-1 cell signature genes are correlated with neuronal development, while Tuft-2 cells are related to immune response. However, it is unknown how these two subsets of Tuft cells function.

Prof. FAN Zusen's group identified Sh2d6 as a signature marker for CD45⁺ Tuft-2 cells. Depletion of Tuft-2 cells resulted in suseptibility to bacterial infection. Tuft-2 cells quickly expanded in response to bacterial infection and sensed the bacterial metabolite N-undecanoylglycine through vomeronasal receptor Vmn2r26. Mechanistically, Vmn2r26 engagement with N-undecanoylglycine activated G-protein-coupled receptor-Phospholipase C gamma2 (GPCR-PLCγ2)-Ca²⁺ signaling axis, which initiated prostaglandin D2 (PGD2) production. PGD2 enhanced mucus secretion of Goblet cells and induced antibacterial immunity. Moreover, Vmn2r26 signaling also promoted SpiB transcriptifactor expression, which is responsible for Tuft-2 cell development and expansion in response to bacterial challenge. This research reveals an additional function of Tuft-2 cells in immunity against bacterial infection through Vmn2r26-mediated recognition of bacterial metabolites.

Figure. Intestinal Tuft-2 cells exert antimicrobial immunity via sensing bacterial metabolite N-undecanoylglycine

Professors TIAN Yong and FAN Zusen from Institute of Biophysics, CAS are corresponding authors. Associate professor XIONG Zhen, senior engineer ZHU Xiaoxiao, graduate students GENG Jingjing and XU Yuwei are co-first authors. This research was supported by the National Key R&D Program of China, National Natural Science Foundation of China, the Beijing Natural Science Foundation and Strategic Priority Research Programs of the Chinese Academy of Sciences.

Contact: FAN Zusen

Institute of Biophysics, Chinese Academy of Sciences

Beijing 100101, China

Email: fanz@ibp.ac.cn

(Reported by Dr. FAN Zusen's group)