Intestinal lymphoepithelial interactions occur in the epithelium and subepithelial space. We asked whether or not lamina propria lymphocytes (LPL) could promote intestinal epithelial cell (IEC) differentiation. In contrast to epithelial cells in UC mucosa, which do not differentiate because of rapid turnover, differentiation of epithelial cells in CD mucosa occurs in the crypts. This dysregulation is driven by alterations in the crosstalk between CD LPL and CD IECs, leading to an acceleration of their differentiation. This alteration seems to involve the transcription factor CDX2 via the activation of the PI3K and MAPK pathways and provides new insights into the dysfunction of the epithelial barrier in CD versus UC. The absence of lymphocytes in Rag1-deficient mice was associated with a defect in colonic IEC differentiation, restored by co-transfer of naïve and regulatory T cells. Interestingly, the transfer of naïve T cells alone induced an acceleration of IEC differentiation similar to what was seen in the colonic mucosa of CD patients. Thus, there is a crosstalk between LPL and IECs that is altered in CD, which leads to an absorptive phenotype of IEC differentiation.