Bmi1 regulates memory CD4 T cell survival via repression of the Noxa gene.
The maintenance of memory T cells is central to the establishment of immunological memory, although molecular details of the process are poorly understood. In the absence of the polycomb group (PcG) gene Bmi1, the number of memory CD4(+) T helper (Th)1/Th2 cells was reduced significantly. Enhanced cell death of Bmi1(-/-) memory Th2 cells was observed both in vivo and in vitro. Among various proapoptotic genes that are regulated by Bmi1, the expression of proapoptotic BH3-only protein Noxa was increased in Bmi1(-/-) effector Th1/Th2 cells. The generation of memory Th2 cells was restored by the deletion of Noxa, but not by Ink4a and Arf. Direct binding of Bmi1 to the Noxa gene locus was accompanied by histone H3-K27 methylation. The recruitment of other PcG gene products and Dnmt1 to the Noxa gene was highly dependent on the expression of Bmi1. In addition, Bmi1 was required for DNA CpG methylation of the Noxa gene. Moreover, memory Th2-dependent airway inflammation was attenuated substantially in the absence of Bmi1. Thus, Bmi1 controls memory CD4(+) Th1/Th2 cell survival and function through the direct repression of the Noxa gene.
Yamashita
Masakatsu
M
Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
Kuwahara
Makoto
M
Suzuki
Akane
A
Hirahara
Kiyoshi
K
Shinnaksu
Ryo
R
Hosokawa
Hiroyuki
H
Hasegawa
Akihiro
A
Motohashi
Shinichiro
S
Iwama
Atsushi
A
Nakayama
Toshinori
T
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003433:Crosses, Genetic; D004247:DNA / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D007156:Immunologic Memory; D016180:Lentivirus Infections / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics*; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency* / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
C489421:Bmi1 protein, mouse; D009687:Nuclear Proteins; C408009:Pmaip1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; D004247:DNA; D063150:Polycomb Repressive Complex 1