The Taste Receptor TAS1R3 Regulates Small Intestinal Tuft Cell Homeostasis

Abstract

Tuft cells are an epithelial cell type critical for initiating type 2 immune responses to parasites and protozoa in the small intestine. To respond to these stimuli, intestinal tuft cells use taste chemosensory signaling pathways, but the role of taste receptors in type 2 immunity is poorly understood. In this study, we show that the taste receptor TAS1R3, which detects sweet and umami in the tongue, also regulates tuft cell responses in the distal small intestine. BALB/c mice, which have an inactive form of TAS1R3, as well as Tas1r3deficient C57BL6/J mice both have severely impaired responses to tuft cell-inducing signals in the ileum, including the protozoa Tritrichomonas muris and succinate. In contrast, TAS1R3 is not required to mount an immune response to the helminth Heligmosomoides polygyrus, which infects the proximal small intestine. Examination of uninfected Tas1r3 2/2 mice revealed a modest reduction in the number of tuft cells in the proximal small intestine but a severe decrease in the distal small intestine at homeostasis. Together, these results suggest that TAS1R3 influences intestinal immunity by shaping the epithelial cell landscape at steady-state.

Cells of the human intestinal tract mapped across space and time

“…Indeed we confirm expression of the succinate receptor, SUCNR1, and downstream mediators GNAT3, PLCB2, ITPR2, PRKCA and TRPM5 (Figure 2E,G), which lead to IL-25-mediated type 2 immune responses. While mouse studies have also implicated TAS1R3 28 , we additionally show expression of TAS1R1, albeit at a lower level. TAS1R1 forms a heterodimer with TAS1R3 for umami sensing to activate the same type 2 immune signaling 26 (Figure 2E,G).…”

Enteric Tuft Cells in Host-Parasite Interactions

“…Increasing evidence (Table 1, Figure 1) suggests that ETCs play major roles in the development of a Th2-dominated host immune response to helminths as well as a murine protozoan, Tritrichomonas [6][7][8][9]23,[56][57][58]. Tritrichomonas muris chronically colonizes the lumen of the distal small intestine and large intestine of mice and elicits colonic Th1 and Th17 cytokine responses as well as an expansion of type 2 innate lymphoid cells (ILC2s) [7,56,59,60].…”

“…Whether ETCs respond to the protozoans Cryptosporidium and Entamoeba remains to be tested even though host resistance in both cases are characterized by Th1 dominant responses [61,62]. Recent discoveries also encourage discussion around ETC functions beyond mobilization of anti-worm responses, such as tissue repair and protection from secondary infections [6,7,9,10,50,57,58,63], and provide additional rationale to study ETC responses to enteric parasites that infect humans and livestock. In response to helminths and protozoans, ETCs produce and release IL-25 (1-4) and cysteinyl leukotrienes (1,2), which subsequently activate the innate lymphoid cell (ILC2) population in the underlying lamina propria via IL-17RB and CYSLTR receptors to produce IL-13, IL-5 and IL-9 [6,7,9,57,64].…”

“…Tuft cells may detect luminal and mucosal signals via a variety of apical and basolateral receptors. They express multiple elements of chemosensory machinery including (i) taste receptors (TAS2Rs and TAS1R3), (ii) components of the taste transduction pathway (G-protein associated subunit α-gustducin and TRPM5), and (iii) metabolite sensing receptors [8,21,23,58]. Additionally, ETCs express receptors for endogenous mediators such as IL-25, GABA and dopamine [22,100,107].…”

Helminth Sensing at the Intestinal Epithelial Barrier—A Taste of Things to Come

“…Interestingly, although tuft cells also produce IL-25 in response to protist-derived succinate via SUCNR1, McGinty et al ( 42 ) demonstrated that stimulation of tuft cells with succinate, although driving IL-25, resulted in no leukotriene production but importantly no defect in ILC2-driven responses. Furthermore, TAS1R3 also expressed on tuft cells responds to Tritrichomonas muris and succinate, but not to a helminth infection ( 45 ), indicating an ability of tuft cells to selectively respond to different parasites.…”