Intraepithelial lymphocytes exhibit selective immunity to intestinal pathogens

Intraepithelial lymphocytes (IEL) are abundant, tissue-resident T cells critical for intestinal immune surveillance, yet their precise roles have remained elusive due to the lack of models enabling their selective genetic ablation. Here, we report the generation ofGzmb-Cre knock-in mice, that when crossed with inducible Diphtheria toxin receptor mice, allows targeted and inducible ablation of IELs without perturbing peripheral immunity. Using this model (referred to as IEL^iDTR), we demonstrate that IELs are dispensable for intestinal homeostasis, including epithelial architecture, barrier function and microbial composition. However, loss of IELs led to increased intestinal infection bySalmonellaTyphimurium andCryptosporidium parvum, but did not affect responses toListeria monocytogenesinfection or DSS colitis. Interestingly, IEL deficiency reduced fecundity of the intestinal nematode,Heligmosomoides polygyrus, despite unaltered worm burden, suggesting a permissive role in helminth colonization. These findings position IELs as evolutionary-tuned sentinels against co-evolved pathogens that can cause lethal diarrheal diseases, and establish the IEL^iDTRmouse as a vital genetic tool for dissecting IEL function in host-pathogen interactionsin vivo.