Background & Aims: T helper (Th) 1 and Th2 cell subsets significantly influence the pathological features of inflammation in the gastrointestinal tract in a distinct manner. It is now established that the transfer of CD4+CD45RBHi (RBHi) T cells to either severe combined immunodeficient (SCID) or recombinase activation gene 2-deficient (RAG-/-) mice results in a severe granulomatous hypertrophic colitis mediated by Th1 cells. We have modified this approach to address the role of Th2 cells. Methods: RBHI T cells from wild-type (Wt) mice or mice genetically predisposed to Th2 responses (interferon-γ-defective [IFN-γ-/-]) with or without B cells were transferred to T cell receptor (TCR)-β and δ-chain-defective (TCR-/-) or SCID mice. Results: Transfer of Wt RBHi T cells induced wasting disease with severe colitis in the TCR-/- mice. In contrast, IFN-γ-/- RBHi T cells induced severe weight loss and hypoalbuminemia without significant inflammation in the colon. The small intestine of these mice exhibited villus atrophy, a decrease in brush-border enzymes, reduced enterocyte proliferation, and an increased number of goblet cells. The presence of B cells was necessary for these changes, because SCID recipients required cotransfer of B cells, together with IFN-γ-/- RBHi T cells for ileal lesions to develop. Treatment of TCR-/- recipients of IFN-γ-/- RBHi T cells with anti-IL-4 mAb abrogated both the wasting disease and the villus atrophy. Conclusions: Dysregulated Th2 cells cause atrophic changes and goblet cell transformation in the small intestinal epithelium and wasting disease mediated by excess interleukin-4 and B cells.