Cutting Edge: PHLPP Regulates the Development, Function, and Molecular Signaling Pathways of Regulatory T Cells

Abstract

Tregs have a reduced capacity to activate the PI3K/Akt pathway downstream of the TCR, and the resulting low activity of Akt is necessary for their development and function. The molecular basis for the failure of Tregs to efficiently activate Akt, however, remained unknown. We show that PH-domain Leucine-rich-repeat Protein Phosphatase (PHLPP), which dephosphorylates Akt, is up-regulated in Tregs, thus suppressing Akt activation. Tregs expressed higher levels of PHLPP than conventional T cells and knock-down of PHLPP1 restored TCR-mediated activation of Akt in Tregs. Consistent with their high Akt activity, the suppressive capacity of Tregs from PHLPP1-/- mice was significantly reduced. Moreover, the development of induced Tregs was impaired in PHLPP1-/- mice. The increased level of Akt's negative regulator, PHLPP, provides a novel mechanism used by T cells to control the Akt pathway and the first evidence for a molecular mechanism underlying the functionally essential reduction of Akt activity in Tregs.

Insulin Inhibits IL-10–Mediated Regulatory T Cell Function: Implications for Obesity

“…This low AKT signaling is functionally relevant for Tregs, because forced activation of the pathway by overexpression of active forms of AKT or deletion of inhibitory phosphatases blocks their normal development and function (14,15,17). We show in this study, however, that unlike TCR or IL-2 stimulation, insulin-induced activation of AKT was significantly higher in Tregs compared with Tconvs, suggesting that Tregs may be uniquely responsive to this hormone.…”

“…Tregs normally have dampened TCR-or IL-2-induced AKT phosphorylation at Ser 473 , at least partly because of high expression of the protein phosphatase PHLPP (15,16). This low AKT signaling is functionally relevant for Tregs, because forced activation of the pathway by overexpression of active forms of AKT or deletion of inhibitory phosphatases blocks their normal development and function (14,15,17).…”

“…Because high AKT activity is associated with loss of Treg function (14,15,17), we asked whether exposure to insulin might affect one or more of these suppressive mechanisms. Tregs and Tconvs were isolated, cultured overnight in 0, 10, or 100 ng/ml insulin to stimulate the AKT pathway, and then stimulated via the TCR.…”

“…For example, relatively low activity of the AKT pathway is essential for the normal development and function of Tregs (14). In addition, fully developed Tregs normally have diminished AKT activity in response to TCR or IL-2 stimulation (15,16), and forced AKT activation inhibits their function (14,15,17). Downstream of AKT, mammalian target of rapamycin (mTOR) activation is also linked to reduced Treg differentiation and function (18)(19)(20), providing a molecular mechanism for why the mTOR inhibitor rapamycin promotes tolerance (21,22).…”

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…The PI3K-AKT-mTOR pathway is a crucial bifurcation point for inflammatory versus regulatory T cell programmes, as the activation of this pathway is required for the polarization and function of most T helper cells but is largely repressed in FOXP3 + T Reg cells 74,75 . AKT function is blunted in T Reg cells by the activity of PTEN, as well as by PH domain leucine-rich repeat-containing protein phosphatases (PHLPPs) that directly inactivate AKT, effectively rewiring their response to IL-2 to selectively activate STAT5, but not AKT [76][77][78] . Removal of this regulation in T Reg cells with PTEN deficiency results in severely compromised T Reg cell stability and in their conversion into inflammatory T H 1 and T H 17 cells 79,80 .…”