T cell intrinsic deletion of the adenomatous polyposis coli gene causes homeostatic proliferation and inflammatory bowel disease (BA11P.142)

• Published in: The Journal of immunology (1950) 2015-05, Vol.194 (1_Supplement), p.184-184.24
• Main Authors: Wong, Chun-Shu, Chen, Chong, Wu, Qi, Liu, Yang, Zheng, Pan
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.194.Supp.184.24

Accumulating data demonstrate a strong association between lymphopenia and autoimmune diseases. However, to our knowledge, none of the known single gene defects that cause lymphopenia are sufficient to cause autoimmune diseases. In addition, the intracellular programing involved in lymphopenia-driven homeostatic proliferation (HP) remains to be elucidated. Using a conditional knockout of adenomatous polyposis coli (Apc) under the control of CD4-cre, we have previously reported that T-cell lineage-specific deletion of the Apc gene causes severe lymphopenia, due to naive T cell death, in part through activation of the cMyc gene. Here, we show that Apc deletion causes both T cell activation, lymphopenia-driven HP. Using this mouse model, we studied the association between lymphopenia-driven HP, and autoimmune diseases. We showed that APC deficiency and the resulting activation of Wnt signaling in T cells causes a fatal inflammatory bowel disease with Crohn’s disease-like pathology. Moreover, using T cells with targeted mutation of beta-catenin, we found that lymphopenia-drivinen HP depends on activation of beta-catenin in T cells, thus providing a missing link between Wnt signaling and homeostatic proliferation. Development of autoimmune diseases requires lymphopenia. This data provide the first genetic evidence that a T-cell intrinsic single-gene defect is sufficient to cause lymphopenia, homeostatic proliferation and autoimmune diseases.