Paper Readig
Graded Foxo1 activity in Treg cells differentiates tumourimmunity from spontaneous autoimmunity
Luo CT, Liao W, Dadi S, Toure A, Li MO
Nature. 2016
Regulatory T(Treg) cells expressing the transcription factor Foxp3 have a pivotal role inmaintaining immunological self-tolerance; yet, excessive Treg cell activities suppress anti-tumour immune responses. Compared to the resting Treg (rTreg) cell phenotype in secondary lymphoid organs, Treg cells in non-lymphoid tissues exhibit an activated Treg (aTreg) cell phenotype. However, the function of aTreg cells and whether their generation can be manipulated are largely unexplored.
In this paper, the researchers found that Foxo1, a transcription factor that has been shown to promote Treg cell suppression of lymphoproliferative disease, played an unexpected role ininhibiting treg-mediated immune tolerance in mice. They found that aTreg cells renewed more slowly than rTreg cells, but not exclusively in non-lysergic tissues. aTreg cell differentiation is associated with foxo1-dependent gene transcription inhibition, with decreased Foxo1 expression, cytoplasmic localization and enhanced phosphorylation at the Akt sites.
The researchers specifically expressed an Akt non-sensitive Foxo1 mutant in Treg cells, demonstrating that it can prevent the down-regulation of lymphoid organ homing molecules and prevent Treg cells from homing to non-netting organs, causing CD8+ T-cell-mediated autoimmune diseases. Tumor-infiltrating Treg cells down-regulated Foxo1 target genes more significantly than those from healthy tissue. Thus, expressing Foxo1mutants at low doses is sufficient to deplete tumor-associated Treg cells, activate effector CD8+ T cells, and inhibit tumor growth without causing autoimmunity.
This study confirmed that aTreg plays acrucial role in inhibiting CD8+ T cell response, and the inactivation of Foxo1 is a necessary condition for aTreg cell migration. It is proposed that Foxo signaling pathway can be activated by fine-tuning in aTreg cells to preferentially destroy tumor immune tolerance.
DOI:10.1038/nature16486
Novel Foxo1-dependent transcriptional programs control Treg cell function
Weiming Ouyang,Will Liao, Chong T et al
Nature. 2012
Treg cell homeostasis and function are dependent on the Treg-cell-specific transcription factor Foxp3, while Treg-cell-lineage commitment is regulated by the Akt kinase and the forkhead box O (Foxo) family of transcription factors. However, whether Foxo proteins act beyond the Treg-cell-commitment stage to control Treg cell homeostasis and function remains largely unexplored.
In this paper, researchers further found that Foxo1 protein is an important regulator of regulatory T cells' function. Regulatory Tcells can express a large number of Foxo1 proteins, which can regulate regulatory T cell (Treg) related genes, suggesting that Foxo protein is a keygene in regulating Treg differentiation. Using Treg cell conditional knock out Foxo1mice, the researchers found that the defective mice developed a fatal inflammatory disease similar in severity to Foxp3 deficient mice, but without regulatory T cell deficiency. The researchers then performed a genome-wide analysis of the Foxo1 binding site and found about 300 foxo1-binding target genes, such as the pro-inflammatory cytokine IFN-γ. These findings suggest that conservative Akt-Foxo1 signaling regulates a genetic process necessary for the functioning of regulatory T cells.
DOI https://doi.org/10.1038/nature11581
Edited by Qianru Huang
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