Altered activation of AKT is required for the suppressive function of human CD4+CD25+ T regulatory cells

Abstract

Suppression by T regulatory cells (Treg IntroductionActive suppression of immune responses by T regulatory cells (Treg cells) is a key mechanism for induction and maintenance of peripheral tolerance. [1][2][3][4] The importance of Treg cells in vivo has been demonstrated in several mouse models: their absence results in systemic autoimmune disease, while their presence can inhibit antitumor, antiallergen, antiviral, and antiparasite immunity. [2][3][4][5] Knowledge of exactly how Treg cells arise, the precise mechanisms that control their suppressive function, and how they differ from effector T cells at the molecular level remains largely unknown. A better understanding of the basic biologic characteristics of Treg cells will lead to novel therapies for diseases resulting from immune dysregulation.Although there is evidence that T cells with a regulatory/ suppressor function exist within all major subsets, most research has been focused on those that are CD4 ϩ and constitutively express high levels of the IL-2R␣ (CD25). These CD4 ϩ CD25 ϩ Treg cells have more recently been further defined based on high expression of the FOXP3 transcription factor, 6,7 and in humans relatively pure populations of CD4 ϩ CD25 ϩ FOXP3 ϩ Treg cells can be isolated from peripheral blood by sorting 1% to 3% of the brightest CD25 ϩ cells within the CD4 ϩ T-cell subset. 8-10 CD4 ϩ CD25 ϩ Treg cells possess several characteristics that suggest their intracellular signaling following T-cell-receptor (TCR) activation may differ from that of effector T cells. For example, activated CD4 ϩ CD25 ϩ Treg cells fail to produce most classic T-cell-derived cytokines, are hyporesponsive in the absence of exogenous growth factors, and suppress the functions of many different cell types. 11,12 The molecular changes, however, that underlie this unique phenotype remain unknown.TCR signaling is initiated by antigen (Ag) binding and results in activation of tyrosine kinases of the Src, Syk, and Tec families and assembly of scaffolds of adaptor molecules. 13 Phosphorylation of these adaptors subsequently leads to activation of downstream effectors, including serine/threonine kinases, such as the mitogenactivated protein kinases (MAPKs) and protein kinase C (PKC), and phosphatidylinositide-3 kinase (PI3ЈK)-dependent serine/ threonine kinases such as AKT. Activation of these cascades results in cytoskeletal rearrangements, cytokine production, cell-cycle progression, and engagement of T-cell effector functions. In contrast, T cells that are functionally hyporesponsive due to activation in the absence of costimulation have a block in activation of the Ras/MAPK pathway and/or in calcium mobilization. 14 A detailed analysis of whether any of these pathways may be altered in human TCR-activated CD4 ϩ CD25 ϩ Treg cells has been hampered by the scarcity of these cells, difficulties in isolating pure populations due to the lack of a reliable cell-surface maker, and their relatively poor proliferation in vitro. Nevertheless, there have been several attempts to chara...

IL-7 Abrogates the Immunosuppressive Function of Human Double-Negative T Cells by Activating Akt/mTOR Signaling

“…Several studies investigated the role of Akt/mTOR signaling in Treg cells. Thereby, enforced activation of Akt or loss of PTEN, an upstream inhibitor of Akt-signaling, resulted in reversal of the suppressive function of Treg cells (41,42). Our results showed that hyperactivation of Akt/mTOR by IL-7 leads to repression of the DN T cell mediated suppression.…”

“…However, Tregs were demonstrated to show diminished Akt pathway activation and an anergic cell fate (41,48). In addition, Tregs and type 1 Tregs initially were characterized as T cells with a special anergic phenotype that is necessary for their suppressive activity (49,50).…”

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 .…”

Foxo in the immune system

“…PKB isoform, which presumably would increase phosphorylated Foxo species, partially reversed the suppressive capacity of regulatory T cells in vitro, associated with restoration of their ability to produce several cytokines such as IFN-g, but not IL-2, without affecting expression levels of Foxp3, CTLA4, CD25, or granzymes A/B (Crellin et al, 2007). Foxo proteins therefore play diverse roles in multiple T cell subsets (Table 1).…”