Intestinal Tuft-2 cells exert antimicrobial immunity via sensing bacterial metabolite N-undecanoylglycine by vomeronasal receptor Vmn2r26

Tuft cells as a type of intestinal epithelial cells exist in epithelial barriers that play a critical role in immunity against parasite infection. It remains elusive about whether Tuft cells participate in bacterial eradication. Here we identify Sh2d6 as a signature marker for CD45+ Tuft-2 cells. Tuft-2 cells are derived from Lgr5+ intestinal stem cells but not bone marrow cells. Depletion of Tuft-2 cells is susceptible to bacterial infection. Tuft-2 cells quickly expand over bacterial infection and sense bacterial metabolite N-undecanoylglycine through vomeronasal receptor Vmn2r26. Mechanistically, Vmn2r26 engagement with N-undecanoylglycine activates GPCR-PLCγ2-Ca2+ signal axis, which initiates prostaglandin D2 (PGD2) production. PGD2 enhances mucus secretion of Goblet cells and induces antibacterial immunity. Moreover, Vmn2r26 signaling also promotes SpiB expression, which is responsible for Tuft-2 cell development and expansion over bacterial challenge. Our findings reveal a novel function of Tuft-2 cells in immunity against bacterial infection through Vmn2r26-mediated recognition of bacterial metabolites. We used microarrays to detail the gene expression of Tuft-2 cells compared with non Tuft-2 epithelial cells under Shigella infection. 3×10^5 Sh2d6+ Tuft cells (EGFP+EpCAM+Siglec-F+), 3×105 Sh2d6− Tuft cells (EGFP−EpCAM+Siglec-F+) and non-Tuft epithelial cells (EpCAM+Siglec-F−) from Sh2d6EGFP mice were sorted by flow cytometer and cells were digested with TRIzol reagent (Invitrogen). RNA quality was monitored using NanoDrop ND-1000. RNA integrity was tested by agarose gel electrophoresis. RNA samples were then assayed with Affymetrix Mouse Transcriptome Array 1.0 (Beijing Cnkingbio Biotechnology).