The Nlrp3 inflammasome is a protein complex responsible for mounting cytokine and cell death responses upon detecting microbial or host-derived stress signals. Nlrp3 variants are associated with Crohn’s Disease (CD) but the cellular origins of these detrimental Nlrp3 signaling effects have not been identified. While Nlrp3 is thought to be expressed only in innate immune cells I have data showing that also small intestinal intra-epithelial lymphocytes (sIELs) express Nlrp3. Moreover, I found that activating Nlrp3 selectively in IELs altered the homeostatic sIEL subset balances. Given their high abundancies throughout the intestine and their strategic inter-epithelial position at the luminal border, these observations suggest that Nlrp3 might regulate inflammation though empowering IELs to patrol for luminal and epithelial stress signals. In this project, I will investigate IEL-specific Nlrp3 functions using mice with IEL-specific Nlrp3 auto-activation. Given the Nlrp3 linkage with CD I will profile IEL inflammasome activities in mice undergoing ileitis as well as in human CD biopsies. Next, I will study Nlrp3 involvement in ileitis by using genetic gain- or loss-of-function mouse models. Finally, I will use an IEL-IEC co-culture system to unravel the mechanisms by which Nlrp3 activation in IELs impacts on inflammation. Understanding the effects of Nlrp3 activation in IELs might reveal novel insights into how disturbances in this signaling pathway regulate CD susceptibility.