Tuft cells promote reactivation of memory Th2 cells and are required for protective immunity to intestinal helminth re-infection.

Small intestinal (SI) tuft cells are critical sentinels for innate type 2 immunity against helminths, but their role in adaptive responses is unclear. We show that despite the presence of protective memory CD4+ T helper 2 (Th2) cells, tuft cells remain essential for worm clearance during a secondary infection with Heligmosomoides polygyrus bakeri (H. polygyrus bakeri). Th2 cells still develop in the absence of tuft cells or group 2 innate lymphoid cells but upregulate receptors for tuft cell effectors interleukin-25 (IL-25) and leukotriene C4 (LTC4) when they enter the SI. IL-25 and LTC4 are sufficient to drive IL-13 production by Th2 cells, and their absence during a secondary infection diminishes IL-13. Complete restriction of a secondary H. polygyrus bakeri infection requires granulomas that reduce worm fitness together with tuft cell-dependent clearance from the intestinal lumen. Thus, tuft cells regulate both innate and adaptive immunity, and we extend the paradigm that Th2 cells require tissue-specific cues for optimal function.