PP2A-dependent control of transcriptionally active FOXO3a in CD8+ central memory lymphocyte survival requires p47phox

Forkhead box O3a (FOXO3a) transcription factor is regulated by complex post-translational modifications that allow for transcriptional control of various apoptosis factors including pro-apoptotic Bim. Although it has been shown that kinases phosphorylate FOXO3a in memory T cells, the role of protein phosphatases in the control of memory T lymphocyte FOXO3a function is less clear. Here, we report that FOXO3a is dephosphorylated (activated) by a protein phosphatase 2A (PP2A)-dependent mechanism in CD8(+) memory lymphocytes (Tm) during Listeria monocytogenes (Lm) infection, which allows for enhanced Bim transcription in nicotinamide adenine dinucleotide phosphate-oxidase p47(phox)-deficient (p47(phox-/-)) Tm. Consequently, CD8(+) Tm from Lm-infected p47(phox-/-) mice express significantly higher levels of each pro-apoptotic Bim protein isoform. Furthermore, there was a profound reduction in the accumulation of CD8(+) T central memory (Tcm) cells in infected p47(phox-/-) spleens, and 65% p47(phox-/-) mouse moribundity following secondary Lm reinfection compared with 25% in wild-type mice. Notably, blocking PP2A activity attenuated FOXO3 activation and Bim transcription in p47(phox-/-) CD8(+) memory lymphocytes. Our findings indicate a critical role for p47(phox) in a dynamic interplay between PP2A and FOXO3a that regulates pro-apoptotic Bim transcription in CD8(+) memory lymphocytes during infection. Cell Death and Disease (2012) 3, e375; doi: 10.1038/cddis.2012.118; published online 23 August 2012