Abstract
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.
Highlights
Bcl-3 is an atypical nuclear factor-kB (NF-kB) family member that regulates NF-kB-dependent gene expression in effector T cells, but a cell-intrinsic function in regulatory T (Treg) cells and colitis is not clear
To study a potential role of Bcl-3 in the pathogenesis of human inflammatory bowel disease (IBD), we used immunohistochemistry to examine Bcl-3 expression levels in colons of patients suffering from either Crohn’s disease (CD) or ulcerative colitis (UC). This staining revealed that CD and UC patients had massive infiltration of Bcl-3 þ cells in the lamina propria (LP), whereas control groups displayed only few Bcl-3 expressing cells within this area (Fig. 1a)
Quantitative reverse transcriptase–PCR (RT–PCR) analysis using RNA isolated from colons of patients with active CD or UC showed significantly increased levels of Bcl-3 expression compared with controls (Fig. 1b)
Summary
Bcl-3 is an atypical NF-kB family member that regulates NF-kB-dependent gene expression in effector T cells, but a cell-intrinsic function in regulatory T (Treg) cells and colitis is not clear. 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 gdT cells, but not ab T cells. In Treg cells, Bcl-3 associates directly with NF-kB p50 to inhibit DNA binding of p50/p50 and p50/p65 NF-kB dimers, thereby regulating NF-kB-mediated gene expression. Treg cells are important mediators of tolerance in the intestine and various studies have linked defects in Treg cell development or function to the onset of IBD10,11. Treg cells in the prevention of IBD is well-appreciated, the molecular factors regulating the functionality of Treg cells during
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
