Bmi1 regulates memory Th2 cell survival via repression of the Noxa gene.

Abstract

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 Th2 cells was reduced significantly. Enhanced cell death of Bmi1−/− memory Th2 cells was observed both in vivo and in vitro. Among various pro‐apoptotic genes that are regulated by Bmi1, the expression of pro‐apoptotic BH3 only protein Noxa was increased in Bmi1−/− effector CD4 T cells even in the absence of Ink4a and Arf. 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 to the Noxa gene was highly dependent on the expression of Bmi1. In addition, DNA methylation appeared to control the recruitment of PcG gene products and the expression levels of Noxa. Moreover, memory Th2‐dependent airway inflammation was attenuated substantially in the absence of Bmi1. Thus, Bmi1 controls memory Th2 cell survival and function through the direct repression of the Noxa gene.