Patients with inflammatory bowel disease (IBD) are at high risk of colorectal cancer (CRC) arising from chronic colitis. Currently, 1-2 million Americans suffer from IBD. CRC occurs in 2% of patients with ulcerative colitis (DC) after 10 years and 19% after 30 years. Therefore, elucidating mechanisms of carcinogenesis in IBD may improve chemoprevention and enhance survival. Recent analyses suggest dysplasia in UC increases with increasing severity, duration, extent and chonicity of inflammation. Data presented here show that T cell activation increases Wnt/p-catenin signaling in intestinal crypts, a pathway known to regulate stem cells in the intestine and elsewhere. Over 90% of CRC contain mutations in Wnt/p-catenin pathway genes. Dysregulated Wnt/p-catenin signaling is detected in 45% of UC-associated CRC. In preliminary studies, we show T cell-induced Wnt/beta-catenin signaling in progenitor populations of crypt epithelial cells. Data indicate that within 3h of T cell activation, nuclear beta-catenin levels and mRNA for p-catenin target genes increase by >200% followed by enhanced c-Myc and CD44 IHC staining (6h) and proliferation (BrdU, Ki67) (12h) of crypt progenitor cells. Involvement of TNFR1/2 and PI3K/Akt signaling was suggested by 40-80% reduction of Wnt/p-catenin signaling in crypt cells from anti-CDS-treated TNFRI/2-/- and Ly-294002 (PI3K inhibitor)-treated mice respectively. Thus, we postulate that engagement of epithelial TNF receptor activates PI3K/Akt signaling which promotes nuclear accumulation of beta-catenin protein, target gene expression and proliferation in crypt progenitor cells. The current proposal tests the hypothesis that TNFR1/2 and PI3K/Akt cooperate to induce Wnt/beta-catenin signaling by using TNFR1/2-/-, TNFR1-/-, TNFR2-/- and Aktr-/- mice as hosts for bone marrow chimera (BMC) mice. Examination of Wnt/beta-catenin signaling in BMC mice will advance our understanding of mechanism(s) regulating lymphoepithelial interactions in IBD.