Type 3 innate lymphoid cells (ILC3s) play a critical role in intestinal immunity by providing an array of cytokines that reinforce the epithelial barrier and keep the enormous symbiotic microbiota at a safe distance. One of these cytokines, interleukin (IL)-22, induces the production of antimicrobial peptides by epithelial cells and inhibits their apoptosis. In this issue, Aparicio-Domingo et al. report that ILC3s and IL-22 protect epithelial stem cells from death induced by methotrexate (MTX), an antifolate drug widely used in treatments against cancer and autoimmunity. ILC3s thereby limit the intestinal pathology associated with such treatments.
Mice treated with MTX rapidly develop intestinal pathology characterized by a loss in Lgr5+ epithelial stem cells and, as a consequence, suffer a decrease in epithelial proliferation and intestinal architecture. However, the mice fully recover seven days after cessation of treatment, via a process involving phosphorylation of the transcription factor Stat3 in epithelial cells and the recovery of full proliferative capacity. In the absence of ILC3s, posttreatment reinduction of Stat3 phosphorylation and epithelial proliferation fails, and the intestine does not heal. Several cytokines are produced by ILC3s in this context, such as GM-CSF, lymphotoxin, IFNγ, and IL-22, but IL-22 was the only one found to activate Stat3 and is required to protect Lgr5+ cells from the deleterious effects of MTX.
These data extend the roles of ILC3s in intestinal immunity: not only do they induce the production of effectors that target microbes, but they also increase epithelial resistance to injury. Together, these effects reinforce the intestinal barrier to allow for a good living for both the host and its symbiotic microbiota. It appears now that ILC3s also protect us from the side effects of chemotherapy, which remains our best shot at fighting tumors. Such side effects may be further attenuated by promoting the activity of ILC3s, for example by delivering agonists of RORγt, a transcription factor and nuclear hormone receptor required for the generation of ILC3s. Conversely, ILC3s and their counterparts in adaptive immunity, the Th17 cells, have been implicated in autoimmunity and IBD, and antagonists of ILC3s and Th17 cells are being developed to combat these types of pathologies. However, it is becoming clear that great care must be taken when considering inhibition of ILC3s, as this inhibition would also be expected to weaken the intestinal barrier.