Enigmatic tuft cells residing in intestine constitutively produce type II immunity primer cytokine IL-25

Type II immunity is responsible for such physiological and pathological conditions as allergy, anti-parasite [anti-worm] expulsion response, thermoregulation and lean body metabolism. Right now our therapeutic toolkit to influence this system is minimal or even nonexistent. We just don't know enough about it [unlike TH1 response].

This new paper in journal Nature is a good example for this scientific gap in type II immunity. Here, the authors, led by Richard Locksley at UCSF, revealed that little known tuft cells residing in intestine contribute to type II immunity by secreting IL-25.

It appears that within intestine we have 5 cell types, 1 absorptive enterocytes, and 4 secretory cell types: paneth, tuft, goblet and enteroendocrine. By using Flare25 mouse knock-in/deleter model, the authors found that in normal mouse intestine, IL-25 was expressed by rare cells that were also positive for EpCam⁺ and doublecortin like kinase 1 (DCLK1⁺). These were markers for tuft cells (EpCam⁺ DCLK1⁺) [IL-25⁺cells were negative (a) for chromogranin A, a marker for enteroendocrine cells, (b) lysozyme, a marker for paneth cells, and (c) mucin 2, a marker for goblet cells].

Next, the authors showed that tuft cells undergo expansion following worm challenge (type II immune response) in a IL-13-dependent manner (produced by group 2 innate lymphoid cells ILC2).

IL-13 producing intestinal ILC2 were in turn supported by IL-25⁺ producing tuft cells in a forward-feed circuit.

Physiological significance of IL-25⁺ tuft cells became evident when the authors showed delay in anti-worm expulsion response in mouse model of epithelial [tuft]-selective deficiency of IL-25 production.

In summary, this study uncovered immunological role of tuft cells in type II immunity. Naturally occurring tuft cell-derived IL-25 support development and maintenance of naturally occurring IL-13⁺ ILC2 and vise versa.

David Usharauli