Helminth-induced reprogramming of the stem cell compartment inhibits type 2 immunity
Danielle Karo‐Atar, Shaida Ouladan, Tanvi Javkar, Loïck Joumier, Macy K. Matheson, Sydney Merritt, Susan Westfall, Annie Rochette, Maria E. Gentile, Ghislaine Fontès, Gregory J. Fonseca, Marc Parisien, Luda Diatchenko, Jakob von Moltke, Mohan Malleshaiah, Alex Gregorieff, Irah L. King
Abstract
Enteric helminths form intimate physical connections with the intestinal epithelium, yet their ability to directly alter epithelial stem cell fate has not been resolved. Here we demonstrate that infection of mice with the parasite Heligmosomoides polygyrus bakeri (Hpb) reprograms the intestinal epithelium into a fetal-like state marked by the emergence of Clusterin-expressing revival stem cells (revSCs). Organoid-based studies using parasite-derived excretory-secretory products reveal that Hpb-mediated revSC generation occurs independently of host-derived immune signals and inhibits type 2 cytokine-driven differentiation of secretory epithelial lineages that promote their expulsion. Reciprocally, type 2 cytokine signals limit revSC differentiation and, consequently, Hpb fitness, indicating that helminths compete with their host for control of the intestinal stem cell compartment to promote continuation of their life cycle.