The cyclin‐dependent kinase inhibitors p27<sup>Kip1</sup> and p21<sup>Cip1</sup> are not essential in T cell anergy

Verdoodt, Berlinda; Blazek, Tino; Rauch, Pia; Steinkasserer, Alexander; Lutz, Manfred B.; Funk, Jens Oliver

doi:10.1002/eji.200323960

Cited by 17 publications

(13 citation statements)

References 49 publications

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“…Kip1 plays a role in promoting anergy, whereas in other models, including our own, this does not appear to be the case (9,10,12,14,29,30). Using the novel cyclophilin ligand SFA, we showed that G 1 phase arrest does not necessarily lead to anergy ( Fig.…”

Section: Discussionmentioning

confidence: 62%

A Role for Mammalian Target of Rapamycin in Regulating T Cell Activation versus Anergy

Zheng

Collins

Lutz

et al. 2007

The Journal of Immunology

248

243

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Whether TCR engagement leads to activation or tolerance is determined by the concomitant delivery of multiple accessory signals, cytokines, and environmental cues. In this study, we demonstrate that the mammalian target of rapamycin (mTOR) integrates these signals and determines the outcome of TCR engagement with regard to activation or anergy. In vitro, Ag recognition in the setting of mTOR activation leads to full immune responses, whereas recognition in the setting of mTOR inhibition results in anergy. Full T cell activation is associated with an increase in the phosphorylation of the downstream mTOR target S6 kinase 1 at Thr421/Ser424 and an increase in the mTOR-dependent cell surface expression of transferrin receptor (CD71). Alternatively, the induction of anergy results in markedly less S6 kinase 1 Thr421/Ser424 phosphorylation and CD71 surface expression. Likewise, the reversal of anergy is associated not with proliferation, but rather the specific activation of mTOR. Importantly, T cells engineered to express a rapamycin-resistant mTOR construct are resistant to anergy induction caused by rapamycin. In vivo, mTOR inhibition promotes T cell anergy under conditions that would normally induce priming. Furthermore, by examining CD71 surface expression, we are able to distinguish and differentially isolate anergic and activated T cells in vivo. Overall, our data suggest that by integrating environmental cues, mTOR plays a central role in determining the outcome of Ag recognition.

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Section: Discussionmentioning

confidence: 62%

A Role for Mammalian Target of Rapamycin in Regulating T Cell Activation versus Anergy

Zheng

Collins

Lutz

et al. 2007

The Journal of Immunology

248

243

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“…Indeed, Sam68 overexpression results in cell cycle arrest in the G 1 phase. 53 Given that recent studies have questioned p27 kip1 and p21 cip as candidates for the block in cell cycle progression, 54 it will be interesting to determine whether Sam68-deficient mice possess a defect in anergy induction or whether it is rather the combined action of multiple redundant mechanisms that keeps self-reactive T cells silent.…”

Section: Discussionmentioning

confidence: 99%

A novel negative regulatory function of the phosphoprotein associated with glycosphingolipid-enriched microdomains: blocking Ras activation

Šmída

Posevitz-Fejfar

Hořejšı́

et al. 2007

Blood

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In primary human T cells, anergy induction results in enhanced p59Fyn activity. Because Fyn is the kinase primarily responsible for the phosphorylation of PAG (the phosphoprotein associated with glycosphingolipid-enriched microdomains), which negatively regulates Srckinase activity by recruiting Csk (the Cterminal Src kinase) to the membrane, we investigated whether anergy induction also affects PAG. Analysis of anergic T cells revealed that PAG is hyperphosphorylated at the Csk binding site, leading to IntroductionIn the thymus, most T cells undergo negative selection as they bind with high affinity to the self-peptide/MHC complexes presented. However, thymic selection is not a tight process and some autoreactive T cells escape into the periphery. 1 To protect the body from these potentially destructive cells, there must exist mechanisms of peripheral tolerance that prevent autoreactive T cells from becoming activated; one such mechanism is anergy. 2 T cells receiving a strong signal via the T-cell receptor (TCR) [signal 1] in the absence of costimulation [signal 2] enter into an unresponsive state (ie, anergy) in which the cells are alive but fail to display functional responses, such as proliferation in response to full activation [signal 1 ϩ 2]. 3,4 Although the mechanism responsible for the induction of anergy remains unknown, the characterization of anergic T cells has clearly demonstrated that the lack of proliferation is due to a block in interleukin-2 (IL-2) production and that anergic T cells proliferate after addition of exogenous IL-2. The defect in IL-2 production is attributed to a block in Ras activation, 5-7 a small G-protein that activates the mitogen-activated protein kinase cascade, ultimately resulting in activation of the transcription factor activator protein-1 (AP-1). Indeed, the ionomycininduced anergy model shows that activation of nuclear factor of activated T cells in the absence of AP-1 and nuclear factor of the -enhancer in B cells (NF-B) leads to the transcription of genes that induce anergy. 8 Within the TCR signaling cascade, the earliest alteration detected in anergic T cells is the up-regulation of the Src family kinase (SFK) p59Fyn. 9,10 However the mechanism by which Fyn contributes to anergy is unknown. In addition to the TCR, 11 Fyn also binds the phosphoprotein associated with glycosphingolipidenriched microdomains (PAG) 12 (also known as the Csk binding protein [Cbp]). 13 Fyn is the kinase responsible for PAG phosphorylation. 14 PAG, a transmembrane adaptor that localizes within the lipid rafts, negatively regulates Src kinase activity by recruiting the C-terminal Src kinase (Csk) to the membrane. 15 Csk in turn phosphorylates the inhibitory tyrosines conserved within the Src kinases. 16 It is noteworthy that T cells overexpressing PAG are resistant to activation via the TCR, a phenotype similar to anergy. 12,17 Therefore, we chose to investigate whether anergy induction leads to changes within PAG that might contribute to the unresponsiveness of anergic T cells. Material...

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“…These forms of anergy do not require p27 kip1 (23,24), most likely because the anergy avoidance signal in these cells has been cut off upstream of p27 kip1 (see Fig. 1).…”

Section: Signals From Il-2r Are Required For T Cells To Escape Anergymentioning

confidence: 97%

New Insights into the Molecular Basis of T Cell Anergy: Anergy Factors, Avoidance Sensors, and Epigenetic Imprinting

Wells

2009

The Journal of Immunology

133

131

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The vertebrate immune system has evolved to deal with invasive pathogens, but this adaptation comes at the expense of immunopathology. Among a number of mechanisms that coevolved to control adaptive immunity is anergy, the functional inactivation of T lymphocytes that respond to Ag in the absence of inflammation. In this review, I highlight a series of intracellular proteins in quiescent T cells that function to integrate signals from Ag, costimulatory, and growth factor receptors. These factors ensure that cells that fail to engage all three pathways are shunted into an alternative transcriptional program designed to dissuade them from participating in subsequent immune responses. Recent studies indicate that anergy is the combined result of factors that negatively regulate proximal TCR-coupled signal transduction, together with a program of active transcriptional silencing that is reinforced through epigenetic mechanisms.

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The cyclin‐dependent kinase inhibitors p27^Kip1 and p21^Cip1 are not essential in T cell anergy

Cited by 17 publications

References 49 publications

A Role for Mammalian Target of Rapamycin in Regulating T Cell Activation versus Anergy

A Role for Mammalian Target of Rapamycin in Regulating T Cell Activation versus Anergy

A novel negative regulatory function of the phosphoprotein associated with glycosphingolipid-enriched microdomains: blocking Ras activation

New Insights into the Molecular Basis of T Cell Anergy: Anergy Factors, Avoidance Sensors, and Epigenetic Imprinting

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The cyclin‐dependent kinase inhibitors p27Kip1 and p21Cip1 are not essential in T cell anergy

Cited by 17 publications

References 49 publications

A Role for Mammalian Target of Rapamycin in Regulating T Cell Activation versus Anergy

A Role for Mammalian Target of Rapamycin in Regulating T Cell Activation versus Anergy

A novel negative regulatory function of the phosphoprotein associated with glycosphingolipid-enriched microdomains: blocking Ras activation

New Insights into the Molecular Basis of T Cell Anergy: Anergy Factors, Avoidance Sensors, and Epigenetic Imprinting

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The cyclin‐dependent kinase inhibitors p27^Kip1 and p21^Cip1 are not essential in T cell anergy