IL-25-induced memory ILC2s mediate long-term small intestinal adaptation.

Area of Science:

• Immunology
• Parasitology
• Gastroenterology

Background:

• Intestinal helminths have evolved mechanisms to modulate host responses, balancing parasite survival with host tissue integrity.
• The interleukin-25 (IL-25) pathway, involving tuft cells and group 2 innate lymphoid cells (ILC2s), plays a role in barrier immunity but can be targeted by parasites.

Purpose of the Study:

• To investigate the long-term consequences of IL-25-induced small intestinal adaptation.
• To characterize the immune cells and mechanisms underlying this adaptation and its impact on host defense.

Main Methods:

• Induction of small intestinal adaptation using IL-25 in a vertebrate model.
• Analysis of anatomical, cellular, and immunological changes in the small intestine.
• Characterization of tissue-resident, memory-effector ILC2s using transcriptomic and epigenetic profiling.
• Assessment of host resistance to barrier pathogens.

Main Results:

• IL-25 induced a persistent small intestinal adaptation with lasting anatomical, cellular, and immunological alterations.
• This adaptation conferred heightened resistance to barrier pathogens, including in the lungs.
• The adaptation was sustained by transcriptionally and epigenetically modified, tissue-resident, memory-effector ILC2s, distinct from innate immune training.
• Epithelial stem cells remained unaltered, and memory ILC2s maintained an activated state without chronic inflammation.

Conclusions:

• IL-25-mediated small intestinal adaptation creates a resilient mucosal barrier through sustained ILC2 memory.
• This pathway offers a strategy for deploying innate immune cells to coordinate distributed mucosal defense, enhancing host resistance without adverse sensitization.