The AKT–mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells

By S. Haxhinasto, D. Mathis, C. Benoist. Journal of Experimental Medicine, 2008

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CD4+Foxp3+ regulatory T (T reg) cells play an essential role in maintaining immunological tolerance via their suppressive function on conventional CD4+ T (Tconv) cells. Repertoire studies suggest that distinct T cell receptor signaling pathways lead to T reg differentiation, but the signals that regulate T reg specification are largely unknown. We identify AKT as a strong repressor of entry into the T reg phenotype in vitro and in vivo. A constitutively active allele of AKT substantially diminished TGF-β–induced Foxp3 expression in a kinase-dependent manner and via a rapamycin-sensitive pathway, implicating the AKT–mammalian target of rapamycin axis. The observed impairment in Foxp3 induction was part of a broad dampening of the typical T reg transcriptional signature. Expression of active AKT at a stage before Foxp3 turn on during normal T reg differentiation in the thymus selectively impaired differentiation of CD4+Foxp3+ cells without any alteration in the positive selection of Tconv. Activated AKT, in contrast, did not affect established Foxp3 expression in T reg cells. These results place AKT at a nexus of signaling pathways whose proper activation has a strong and broad impact on the onset of T reg specification.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/6ead0658a8a3499308cd5da09581c7a644b6eadb

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Citations in the corpus

mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “…T cell maturation, as rapamycin promotes the differentiation and expansion of CD4+FoxP3+ Regulatory T cells and CD8+ memory T cells while suppressing CD8+ and CD4+ effector T cell populations (Araki et al., 2009; Haxhinasto et al., 2008), consistent with the metabolic profiles of these cell types.”
Cutting Edge: Distinct Glycolytic and Lipid Oxidative Metabolic Programs Are Essential for Effector and Regulatory CD4+ T Cell Subsets (2011, background): “Inhibition of mTOR can result in the elevated oxidation of exogenous FA (15) and promote Treg differentiation (16).”
Regulatory T Cells and Human Disease. (2020, background): “In addition, activation of the AKT signaling pathway impairs the development of natural Tregs; and inhibitors of the pathway, for example, rapamycin, can induce FoxP3 when combined with premature termination of TCR signaling (174, 175).”
Interleukin-2 Receptor Signaling: At the Interface between Tolerance and Immunity (2010, positive): “In addition, mTOR is also necessary for CD4+ effector Th1, Th2, and Th17 cells while repressing Treg cell formation (Delgoffe et al., 2009; Haxhinasto et al., 2008).”
The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. (2009, background): “Recent studies have shown that T cells expressing a constitutively active Akt failed to upregulate Foxp3 (Haxhinasto et al., 2008).”
Regulatory T Cells: Mechanisms of Differentiation and Function (2012, positive): “Early blockade of PI3K signaling through the use of PI3K-mTOR inhibitors after 18 h of stimulation resulted in robust induction of Foxp3 (125), and sustained Akt activation inhibited the stable induction of Foxp3 in peripheral Foxp3− CD4+ T cells (126).”
Control of regulatory T cell lineage commitment and maintenance (2009, result): “Consistent with these findings, the Mathis and Benoist group showed that sustained Akt activation inhibits stable Foxp3 induction in peripheral Foxp3 CD4+ T cells (Haxhinasto et al., 2008).”
PD-L1 regulates the development, maintenance, and function of induced regulatory T cells (2009, background): “In particular, Akt signaling is essential for naive T cell activation and proliferation but dispensible for T reg cell development and function (Battaglia et al., 2006; Coenen et al., 2007; Gao et al., 2007; Qu et al., 2007; Strauss et al., 2007; Haxhinasto et al., 2008; Sauer et al., 2008).”
HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells (2011, background): “Rapamycin has been shown to potentiate Treg cell differentiation (Haxhinasto et al., 2008; Sauer et al., 2008; Cobbold et al., 2009).”