Elevated levels of Bcl-3 inhibits Treg development and function resulting in spontaneous colitis

5 years ago

Elevated levels of Bcl-3 inhibits Treg development and function resulting in spontaneous colitis

F. Thomas Wunderlich, Nadine Hövelmeyer, Kathrin Davari, Benno Weigmann, Markus F. Neurath, Christian Gallus, Joumana Masri, Sonja Reißig, Katharina Gerlach, Ilgiz A. Mufazalov, Yilang Tang, Alexei Nikolaev, Peter R. Galle, Ari Waisman, Jörn M. Schattenberg, Elke Glasmacher, Christine Wolf

Bcl-3 is an atypical NF-κB family member that regulates NF-κB-dependent gene expression in effector T cells, but a cell-intrinsic function in regulatory T (Treg) cells and colitis is not clear. Here we show that Bcl-3 expression levels in colonic T cells correlate with disease manifestation in patients with inflammatory bowel disease. Mice with T-cell-specific overexpression of Bcl-3 develop severe colitis that can be attributed to defective Treg cell development and function, leading to the infiltration of immune cells such as pro-inflammatory γδT cells, but not αβ T cells. In Treg cells, Bcl-3 associates directly with NF-κB p50 to inhibit DNA binding of p50/p50 and p50/p65 NF-κB dimers, thereby regulating NF-κB-mediated gene expression. This study thus reveals intrinsic functions of Bcl-3 in Treg cells, identifies Bcl-3 as a potential prognostic marker for colitis and illustrates the mechanism by which Bcl-3 regulates NF-κB activity in Tregs to prevent colitis.

Publisher URL: http://www.nature.com/articles/ncomms15069

DOI: 10.1038/ncomms15069