Akt Is a Neutral Amplifier for Th Cell Differentiation

Arimura, Yutaka; Shiroki, Fumiko; Kuwahara, Shingo; Kato, Hidehito; Dianzani, Umberto; Uchiyama, Takehiko; Yagi, Junji

doi:10.1074/jbc.m309063200

Cited by 35 publications

(26 citation statements)

References 60 publications

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“…A number of PIP3-dependent kinases have also been implicated in the regulation of Th1 and Th2 differentiation: Itk and Pdk1 were reported to be required for Th2 differentiation (17,35), whereas Akt has been shown to promote both Th1 and Th2 differentiation (36,37). Our results are most consistent with PI3K signaling being required for both Th1 and Th2 differentiation, without preferential skewing toward either differentiation pathway.…”

Section: Discussionsupporting

confidence: 80%

The p110δ Isoform of Phosphoinositide 3-Kinase Controls Clonal Expansion and Differentiation of Th Cells

Okkenhaug

Patton

Bilancio

et al. 2006

The Journal of Immunology

188

207

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The role of PI3K in T cell activation and costimulation has been controversial. We previously reported that a kinase-inactivating mutation (D910A) in the p110δ isoform of PI3K results in normal T cell development, but impaired TCR-stimulated cell proliferation in vitro. This proliferative defect can be overcome by providing CD28 costimulation, which raises the question as to whether p110δ activity plays a role in T cell activation in vivo, which occurs primarily in the context of costimulation. In this study, we show that the PI3K signaling pathway in CD28-costimulated p110δD910A/D910A T cells is impaired, but that ERK phosphorylation and NF-κB nuclear translocation are unaffected. Under in vitro conditions of physiological Ag presentation and costimulation, p110δD910A/D910A T cells showed normal survival, but underwent fewer divisions. Differentiation along the Th1 and Th2 lineages was impaired in p110δD910A/D910A T cells and could not be rescued by exogenous cytokines in vitro. Adoptive transfer and immunization experiments in mice revealed that clonal expansion and differentiation in response to Ag and physiological costimulation were also compromised. Thus, p110δ contributes significantly to Th cell expansion and differentiation in vitro and in vivo, also in the context of CD28 costimulation.

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Section: Discussionsupporting

confidence: 80%

The p110δ Isoform of Phosphoinositide 3-Kinase Controls Clonal Expansion and Differentiation of Th Cells

Okkenhaug

Patton

Bilancio

et al. 2006

The Journal of Immunology

188

207

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“…Suzuki et al (42) showed that mice lacking PTEN, which is a phosphatase for PIP3, exhibit enhancement of PI3K signal pathway and increase in both Th1 and Th2 cytokine production. Arimura et al (43) demonstrated that overexpression of Akt, a major downstream target of PI3K, resulted in amplification of both Th1 and Th2 development. Furthermore, Schaeffer et al (44) have reported that Tec family tyrosine kinase Itk, which is also regulated by PI3K, has an important role for Th2 development.…”

Section: Cd4mentioning

confidence: 99%

ICOS-Mediated Costimulation on Th2 Differentiation Is Achieved by the Enhancement of IL-4 Receptor-Mediated Signaling

Watanabe¹,

Watanabe²,

Hara

et al. 2005

The Journal of Immunology

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ICOS is the third member of the CD28 family molecules and plays a critical role in many T cell-dependent immune responses. Although accumulated data suggest that ICOS costimulatory signals play an important role in Th2-mediated immune responses, the molecular basis for this selective differentiation mechanism is largely unknown. To clarify this mechanism, we used DO11.10 TCR transgenic ICOS−/− mice and evaluated the nature of ICOS costimulatory signals during the process of Ag-specific activation and differentiation of naive CD4+ T cells. Results obtained from these experiments demonstrated that Ag stimulation of naive CD4+ T cells in the absence of an ICOS signal resulted in impaired Th2 development. Unlike previous reports, we found that primary IL-4 production by these T cells was intact and that IL-4R sensitivity of these T cells was reduced as evidenced by a profound defect in IL-4-induced Stat6 phosphorylation and the early induction of GATA-3. The fact that ICOS ligation of wild-type T cells significantly enhanced IL-4-induced Stat6 phosphorylation and primary GATA-3 induction, but not IL-4 transcription, of naive CD4+ T cells was consistent with the results obtained from ICOS−/− T cell experiments. These observations led us to propose that the predominant effect of ICOS-mediated costimulation on Th2 differentiation is achieved by the enhancement of IL-4R-mediated signaling.

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“…31,32 We observed a profound defect in the capacity of CD4 ϩ CD25 ϩ Treg cells to activate AKT upon stimulation via CD3 and CD28 and, after 10 minutes, the increase in levels of phospho-AKT (Ser473) was only 1.8-fold Ϯ 0.17-fold in CD4 ϩ CD25 ϩ Treg cells compared with 3.2-fold Ϯ 0.58-fold in CD4 ϩ CD25 Ϫ T cells (P Ͻ .001, n ϭ 11; Figure 2A). Analysis more than 30 minutes following stimulation revealed that the reduction in phosphorylation of Ser473 was not due to altered kinetics of activation.…”

Section: Human Cd4 ؉ Cd25 ؉ Treg Cells Have a Reduced Capacity To Phomentioning

confidence: 99%

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

Crellin

García

Levings

2006

Blood

204

181

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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...

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Akt Is a Neutral Amplifier for Th Cell Differentiation

Cited by 35 publications

References 60 publications

The p110δ Isoform of Phosphoinositide 3-Kinase Controls Clonal Expansion and Differentiation of Th Cells

The p110δ Isoform of Phosphoinositide 3-Kinase Controls Clonal Expansion and Differentiation of Th Cells

ICOS-Mediated Costimulation on Th2 Differentiation Is Achieved by the Enhancement of IL-4 Receptor-Mediated Signaling

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

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