Background: In the intestinal epithelium, activation of PI-3 Kinase/AKT pathways, via growth factor-mediated signaling, have been shown to regulate cell proliferation and inhibit apoptosis. An immune activated receptor critical for Th2 immune responses, IL-4R can also activate PI-3 Kinase via IRS-dependent signaling. Herein, using the intestinal goblet cell-specific gene, RELM, we investigate the effect of PI-3 Kinase activation via Th2 immune responses on the goblet cell phenotype. Methods and Results: IL-13 stimulation activated PI-3 Kinase and AKT signal transduction in LS174T cells. Pharmacologic inhibition of PI-3 Kinase and AKT1/2 not only inhibited RELM induction by IL-13 but AKT inhibition also significantly reduced constitutive basal expression of RELM, a response reproduced by the simultaneous pharmacologic inhibition of both EGFR and IGFR signaling. In vivo, the disruption of PTEN, an inhibitor of PI-3 Kinase activation, led to the activation of RELM expression in the small intestine. Furthermore, induction of an intestinal Th2 immune response by infection with a small intestinal nematode parasite, Heligmosomoides polygyrus, led to enhanced epithelial cell proliferation, activation of AKT, as demonstrated by the loss of FOXO1 nuclear localization, and robust induction of RELM expression in wild-type, but not IL-4R knockout mice. Conclusion: These results demonstrate that Th2 immune responses can regulate goblet cell responses by activation of PI-3 Kinase and AKT pathways via IL-4R.