Abstract The intestinal epithelium is comprised of a monolayer of intestinal epithelial cells (IEC), which provide, among other functions, a physical barrier between the high Ag content of the intestinal lumen and the sterile environment beyond the epithelium. IEC express a nonclassical MHC class I molecule known as the thymus leukemia (TL) Ag. TL is known to interact with CD8αα-expressing cells, which are abundant in the intestinal intraepithelial lymphocyte compartment. In this report, we provide evidence indicating that expression of TL by IEC modulates the cytokine profile of CD4+ T cells favoring IL-17 production. We show in an adoptive transfer model of colitis that donor-derived cells become more pathogenic when TL is expressed on IEC in recipient animals. Moreover, TL+IEC promote development of IL-17–mediated responses capable of protecting mice from Citrobacter rodentium infection. We also show that modulation of IL-17–mediated responses by TL+IEC is controlled by the expression of CD8α on CD4+ T cells. Overall, our results provide evidence for an important interaction between IEC and CD4+ T cells via TL, which modulates mucosal immune responses.