IL-25-induced memory type 2 innate lymphoid cells enforce mucosal immunity
Victor S. Cortez, Sara Viragova, Satoshi Koga, Meizi Liu, Claire E. O’Leary, Roberto R. Ricardo-González, Andrew Schroeder, Nathan Kochhar, Dedeepya Vaka, Dario Boffelli, Ophir D. Klein, Michael Diamond, Hong-Erh Liang, Richard M. Locksley
Abstract
Adaptation of intestinal helminths to vertebrates involved the evolution of strategies to attenuate host tissue damage to support parasite reproduction and dissemination of offspring to the environment. Helminths initiate the IL-25-mediated tuft cell-type 2 innate lymphoid cell (ILC2) circuit that enhances barrier protection of the host, although viable parasites can target and limit this pathway. We used IL-25 alone to create small intestinal adaptation, marked by anatomic and immunologic changes that persisted months after induction. Adaptation was associated with heightened resistance to barrier pathogens, including in the lung, and was enforced by transcriptionally and epigenetically modified effector-memory ILC2s distinct from those described by innate "training"; epithelial stem cells remained unaltered. Despite requiring IL-25 for induction, effector-memory ILC2s maintained an activated state in the absence of multiple alarmins and supported mucosal resilience while avoiding adverse sensitization to chronic inflammation, revealing a pathway for deploying innate immune cells to coordinate a distributed mucosal defense.