c-Fos enhances the survival of thymocytes during positive selection by upregulating Bcl-2.
T cells are derived from progenitor thymocytes, of which only a minority receive the appropriate TCR signal, undergo positive selection and mature. Owing to the very short lifespan of thymocytes, the prerequisite for positive selection is survival. TCR signal-induced Bcl-2 expression is believed to play a dominant role in the survival of positively selecting thymocytes, but how Bcl-2 is directly regulated is unknown. Here we report that the immediate early gene (IEG) c-Fos can stimulate the expression of Bcl-2, depending on a specific AP-1-binding site in the Bcl-2 promoter. In c-Fos transgenic (Fos-Tg) mice, c-Fos binds to this site and promotes the expression of Bcl-2. As a result, Fos-Tg thymocytes exhibited enhanced survival, and more mature single-positive (SP) thymocytes were generated, even on a unique TCR background. The TCR repertoire remained normal in Fos-Tg mice. Our results identified c-Fos as the mediator of the stimulatory effect of TCR signaling on Bcl-2 expression. Therefore, c-Fos, as an IEG, because of its early response ability, can quickly rescue the survival of short-lived thymocytes during positive selection. Our results provide novel insight into the mechanism regulating the survival of positively selecting thymocytes.
Wang
Xiaoming
X
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Zhang
Yafeng
Y
Xiao
Gang
G
Gao
Xiang
X
Liu
Xiaolong
X
D000818:Animals; D001665:Binding Sites; D002470:Cell Survival; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D012641:Selection, Genetic; D013950:Thymus Gland / Q000166:cytology*; D015854:Up-Regulation / Q000235:genetics*
D019253:Proto-Oncogene Proteins c-bcl-2; D016760:Proto-Oncogene Proteins c-fos; D011948:Receptors, Antigen, T-Cell