Cutting Edge: Foxp1 Controls Naive CD8+ T Cell Quiescence by Simultaneously Repressing Key Pathways in Cellular Metabolism and Cell Cycle Progression

Abstract

Previously we have shown that transcription factor Foxp1 plays an essential role in maintaining naive T cell quiescence; in the absence of Foxp1, mature naive CD8+ T cells proliferate in direct response to homeostatic cytokine IL-7. Here we report that the deletion of Foxp1 in naive CD8+ T cells leads to enhanced activation of PI3K/Akt/mTOR signaling pathway and its downstream cell growth and metabolism targets in response to IL-7. We found that Foxp1 directly regulates Pik3ip1, a negative regulator of PI3K. In addition, we found that deletion of Foxp1 in naive CD8+ T cells results in increased expression levels of E2fs, the critical components for cell cycle progression and proliferation, in a manner that is not associated with increased phosphorylation of retinoblastoma protein (Rb). Taken together, our studies suggest that Foxp1 enforces naive CD8+ T cell quiescence by simultaneously repressing key pathways in both cellular metabolism and cell cycle progression.

Epigenomic Profiling of Human CD4+ T Cells Supports a Linear Differentiation Model and Highlights Molecular Regulators of Memory Development

“…Confirming this, we found that T cell-specific depletion of Foxp1 protein expression in Foxp1 conditional-deficient mice resulted in loss of the naive CD44 low phenotype in T cells ( Figure 5A). These findings together with published data (Feng et al, 2011;Wei et al, 2016), support the view that Foxp1 acts as a ''naive-keeping'' factor for T cells. Analyses of DNA-meth in our datasets revealed a DMR in the FOXP1 locus, which displayed a strong progressive gain of methylation with differentiation (Tn < Tcm < Tem), which was classified as a selective active promoter in Tn cells ( Figure 5B) based on the displayed histone modification patterns (by EpiCSeg, Mammana and Chung, 2015).…”

“…As for the second class of TFs, we identified FOXP1 as one of the top candidates, a less well known but functionally confirmed Tmem regulator in mice (Feng et al, 2011;Wei et al, 2016). Our present analyses support a similar function in human CD4 + Tmem and additionally unravel the epigenetic control of the FOXP1 gene.…”

Increased DNA methylation variability in type 1 diabetes across three immune effector cell types

“…Indeed, the same signalling pathways have been implicated in differentiation, proliferation and metabolism of both T cells and monocytes49505152. For example, deletion of Foxp1 in naïve CD8 + T cells leads to activation of the mTOR signalling cascade53, indicating a relationship between gene modules 1 and 3 of the regulatory network we identified here (Fig. 4f).…”

Anaerobic Bacterial Fermentation Products Increase Tuberculosis Risk in Antiretroviral-Drug-Treated HIV Patients

“…Butyrate strongly induces FoxP1 mRNA in both CD4 + and CD8 + lymphocytes. FoxP1 is a repressor that inhibits lymphocyte development as well as CD4 + , CD8 + , and B cell activation (Durek et al, 2016; Feng et al, 2011; Stephen et al, 2014; Wang et al, 2014; Wei et al, 2016). FoxP1 is a candidate to mediate some of the inhibitory effects of SCFA on CD4 + and CD8 + lymphocyte mediated immune response, but the role of FoxP1 induction by SCFA in the lung host microbial interface needs confirmation in animal models with cell specific conditional deletion.…”