Higher expression of Bax in regulatory T cells increases vascular inflammation.
This study is to examine our hypothesis that CD4+CD25(high)Foxp3+ regulatory T cells (Tregs) have an interleukin-2 (IL-2) withdrawal-triggered apoptosis pathway, and modulation of Treg apoptosis pathway affects development of vascular inflammation. We found that pro-apoptotic protein Bax upregulation in Tregs is induced by IL-2 withdrawal. Treg apoptosis induced by IL-2 withdrawal is inhibited by a Bax inhibitor, suggesting that highly expressed Bax is functional. To define the role of upregulated Bax in Treg apoptosis, we established a Tregs-specific Bax transgenic mouse model. Enforced expression of Bax in Tregs promotes Treg apoptosis triggered by IL-2 withdrawal and other apoptosis stimuli, suggesting pro-apoptotic role of highly expressed Bax in wild-type Tregs. Finally, higher expression of Bax in Tregs decreases the striking threshold of vascular inflammation due to the failure of suppression of inflammatory cells resulting from Treg apoptosis. These results have demonstrated the proof of principle that the modulation of Tregs apoptosis/survival could be used as a new therapeutic approach for inflammatory cardiovascular diseases.
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19410, USA.
Zeyu
Z
Xiong
Jian
J
Song
Yan
Y
Yan
Yajue
Y
Huang
Alan
A
Cowan
Hong
H
Wang
Xiao-Feng
XF
Yang
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D005263:Femoral Artery / Q000276:immunology / Q000503:physiopathology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014652:Vascular Diseases / Q000276:immunology / Q000503:physiopathology*; D014657:Vasculitis / Q000276:immunology / Q000503:physiopathology; D051028:bcl-2-Associated X Protein / Q000235:genetics*
D015703:Antigens, CD; C494826:BAX protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D051028:bcl-2-Associated X Protein