Abstract
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 p47phox-deficient (p47phox−/−) Tm. Consequently, CD8+ Tm from Lm-infected p47phox−/− 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 p47phox−/− spleens, and 65% p47phox−/− mouse moribundity following secondary Lm reinfection compared with 25% in wild-type mice. Notably, blocking PP2A activity attenuated FOXO3 activation and Bim transcription in p47phox−/− CD8+ memory lymphocytes. Our findings indicate a critical role for p47phox in a dynamic interplay between PP2A and FOXO3a that regulates pro-apoptotic Bim transcription in CD8+ memory lymphocytes during infection.
Highlights
Our findings demonstrate a novel role for protein phosphatase 2A (PP2A)-dependent forkhead box O3a (FOXO3a) activation, and indicate p47phox is critical in the dynamic interplay between PP2A and Forkhead box O3a (FOXO3a) that regulates pro-apoptotic Bim transcription in CD8 þ memory lymphocytes during infection
Before Listeria monocytogenes (Lm) infection the percentages of CD4 þ and CD8 þ lymphocytes as well as IFNg expression in p47phox À / À spleens was similar to WT spleens (Supplementary Figure 1), notably, fewer CD4 þ and CD8 þ T lymphocytes accumulated in Lm-infected p47phox À / À spleens than WT
Lm infection, which suggest that the selective expansion of CD8 þ T central memory (Tcm) is impaired in p47phox À / À mice. These findings reveal that the Lm elicited peak CD8 þ effector lymphocyte response on post infection day 7, and the mounting CD8 þ central memory lymphocyte response are distinct in WT and Nox2-reactive oxygen species (ROS)-deficient p47phox À / À and gp91phox À / À mice
Summary
P47phox À / À T lymphocyte responses to primary Lm infection. We reported microenvironment cues within p47phox-deficient secondary lymphoid organs suppress p47phox À / À CD8 þ lymphocyte death in vivo.[14]. We found that fewer total and Ova[257-264] antigen-specific CD8 þ T cells accumulated in p47phox À / À and gp91phox À / À spleens 7 days after infection than treated WT spleens (Figure 2b). Similar to the primary CD8 þ response to Lm, significantly more effector, Tem and Tec, cells accumulated in the spleens of p47phox À / À mice that survived secondary Lm reinfection than treated WT mice (Figures 3a and b). These findings demonstrate that PP2A regulates FOXO3a activity in CD8 þ memory lymphocytes and indicate that p47phox is necessary for regulating PP2A activity These investigations suggest that the selective expansion of CD8 þ Tcm is compromised in p47phox À / À mice during Lm infection because in the absence of p47phox FOXO3a is transcriptionally activated by a PP2A-dependent mechanism that allows for unchecked Bim expression
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