It is increasingly recognized that CD1d-restricted immune responses play an important function within the microbial-epithelial-immune interface of the intestines. CD1d-restricted immune responses are essential for the regulation of microbial commensalism and the responses to pathogens. In turn, microbes regulate invariant natural killer T (iNKT) cells in intestinal tissues. Under germ-free or antibiotic-mediated, germ-reduced conditions iNKT cell numbers are increased in intestines. The mechanistic basis for this increase is likely derived from diminished microbial induced inhibition of chemotactic factors (e.g. CXCL16) and the lack of microorganisms that possess inhibitory glycosphingolipids (e.g. Bacteroides fragilis) under these circumstances. In the setting of germ reduction, mucosal tissues such as the colon also become highly sensitive to environmental stimuli that trigger the activation of CD1d-dependent inflammatory pathways, using oxazolone-induced colitis as a model. This microbial dependent regulation of iNKT cells and consequently sensitivity to oxazolone administration is age dependent wherein microbial colonization during a critical neonatal window is essential for the normalization of iNKT cells and decreased sensitivity to oxazolone. We thus hypothesized that oxazolone is a model for an environmental trigger of intestinal inflammation in a susceptible host. Oxazolone is a small molecule that is based on a core oxazole structure and long considered as a hapten although the exact mechanism by which oxazolone causes intestinal inflammation is unknown. When administered to the mucosa, oxazolone induces a CD1d-dependent inflammatory response and intestinal injury due to excessive type 1 and type 2 cytokines derived from the hematopoietic system depending upon the genetic background of the host. The intestinal inflammation induced by topical administration of oxazolone is impeded by an IL-10 mediated anti-inflammatory response derived from the intestinal epithelial cell (IEC) and potentially specific elements of the hematopoietic system. In the case of the IEC, such IL-10 production is dependent upon IEC expression of microsomal triglyceride transfer protein (MTP), which regulates CD1d function, and CD1d itself. When Mttp or Cd1d are conditionally deleted from the IEC, CD1d-dependent IL-10 production is diminished and oxazolone-induced colitis is significantly more severe. This presentation will focus on new insights into environmental and microbial derived factors that mimic these responses.