Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and IFN-γ but not TH2 cytokines

Kane, Larry; Andres, Pietro G.; Howland, Kimberly C.; Abbas, Abul K.; Weiss, Arthur

doi:10.1038/83144

Cited by 298 publications

(246 citation statements)

References 76 publications

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“…In addition to ROI production being controlled through the TCR, we also document that signaling through CD28 induces transient ROI production. These results reinforce the idea that while some aspects of T cell activation such as up-regulation of glycolysis, Bcl-x L , and IL-4 (44 -46) are more directly regulated by costimulatory signaling, other events such as IL-2 and IFN-␥ production use costimulation to amplify signals from the TCR (47).…”

Section: Discussionsupporting

confidence: 82%

The Requirement of Reversible Cysteine Sulfenic Acid Formation for T Cell Activation and Function

Michalek

Nelson

Holbrook

et al. 2007

The Journal of Immunology

101

102

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Reactive oxygen intermediates (ROI) generated in response to receptor stimulation play an important role in mediating cellular responses. We have examined the importance of reversible cysteine sulfenic acid formation in naive CD8+ T cell activation and proliferation. We observed that, within minutes of T cell activation, naive CD8+ T cells increased ROI levels in a manner dependent upon Ag concentration. Increased ROI resulted in elevated levels of cysteine sulfenic acid in the total proteome. Analysis of specific proteins revealed that the protein tyrosine phosphatases SHP-1 and SHP-2, as well as actin, underwent increased sulfenic acid modification following stimulation. To examine the contribution of reversible cysteine sulfenic acid formation to T cell activation, increasing concentrations of 5,5-dimethyl-1,3-cyclohexanedione (dimedone), which covalently binds to cysteine sulfenic acid, were added to cultures. Subsequent experiments demonstrated that the reversible formation of cysteine sulfenic acid was critical for ERK1/2 phosphorylation, calcium flux, cell growth, and proliferation of naive CD8+ and CD4+ T cells. We also found that TNF-α production by effector and memory CD8+ T cells was more sensitive to the inhibition of reversible cysteine sulfenic acid formation than IFN-γ. Together, these results demonstrate that reversible cysteine sulfenic acid formation is an important regulatory mechanism by which CD8+ T cells are able to modulate signaling, proliferation, and function.

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Section: Discussionsupporting

confidence: 82%

The Requirement of Reversible Cysteine Sulfenic Acid Formation for T Cell Activation and Function

Michalek

Nelson

Holbrook

et al. 2007

The Journal of Immunology

101

102

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“…Similar to Malstrom et al [37], the mAkt transgenic lines described here developed lymphoblastic lymphomas. Retroviral transduction of Akt in vitro has also been shown to increase T cell activation and production of IL-2 and IFN-+ but not IL-4 [39]. In addition, T cell-specific Akt-transgenic mice have been previously described to accumulate CD4 T cells and B cells with age and to develop autoimmunity [40].…”

Section: Discussionmentioning

confidence: 99%

Activated Akt promotes increased resting T cell size, CD28‐independent T cell growth, and development of autoimmunity and lymphoma

et al. 2003

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The mechanisms that regulate basal T cell size and metabolic activity are uncertain. Since the phosphatidylinositol-3 phosphate kinase (PI3 K) and Akt (PKB) pathway has been shown in model organisms to regulate both cell size and metabolism, we generated transgenic mice expressing a constitutively active form of Akt (myristoylated Akt, mAkt) in T cells. Naive transgenic T cells were enlarged and had increased rates of glycolysis compared to control T cells. In addition, mAkt transgenic T cells resisted death-by-neglect upon in vitro culture. Upon activation, mAkt-transgenic T cells were less dependent than control cells on costimulation through CD28 and could both grow rapidly and secrete cytokines in the absence of CD28 ligation. In addition, transgenic expression of mAkt led to the accumulation of CD4 T cells and B cells with age. Many aged mAkt-transgenic mice also developed autoimmunity with immunoglobulin deposits on kidney glomeruli and displayed increased incidence of lymphoma. Together, these data show that Akt activation is sufficient to increase basal T cell size and metabolism. Enhancement of T cell metabolism by Akt and more rapid CD28-independent T cell growth may contribute to the accumulation of excess immune cells and the development of lymphoma and autoimmunity.

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“…It also recruits both Akt and PDK-1 to the plasma membrane through the binding of these active lipid products to the pleckstrin homology (PH) domains of Akt and PDK-1, allowing for direct phosphorylation of Akt by PDK-1 at Thr 308 (24). Therefore, the phosphorylation state of Akt can be used as a surrogate indicator of PI3-K activation (22,35). To examine whether Cbl-b downregulates PI3-K/Akt activity in T cells, both WT and Cbl-b Ϫ/Ϫ T cells were stimulated with anti-CD3 Ab with or without anti-CD28 Ab and lysed.…”

Section: Cblmentioning

confidence: 99%

T-Cell Receptor-Induced NF-κB Activation Is Negatively Regulated by E3 Ubiquitin Ligase Cbl-b

Qiao

Molinero

et al. 2008

Molecular and Cellular Biology

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Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and IFN-γ but not TH2 cytokines

Cited by 298 publications

References 76 publications

The Requirement of Reversible Cysteine Sulfenic Acid Formation for T Cell Activation and Function

The Requirement of Reversible Cysteine Sulfenic Acid Formation for T Cell Activation and Function

Activated Akt promotes increased resting T cell size, CD28‐independent T cell growth, and development of autoimmunity and lymphoma

T-Cell Receptor-Induced NF-κB Activation Is Negatively Regulated by E3 Ubiquitin Ligase Cbl-b

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