A Novel ERK-dependent Signaling Process That Regulates Interleukin-2 Expression in a Late Phase of T Cell Activation

Koike, Toru; Yamagishi, H; Hatanaka, Yasue; Fukushima, Atsuki; Chang, Jing-Wen; Xia, Yan; Fields, Mark; Chandler, Phillip; Iwashima, Makio

doi:10.1074/jbc.m210829200

Cited by 72 publications

(73 citation statements)

References 40 publications

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“…Sustained Erk signaling induced by Ag binding to the TCR is required for full activation of T cells and their effector functions, such as IL-2 production (20,22,23). It was reported that B-Raf mediates sustained Erk activation (18)(19)(20), but the molecular mechanism of how stimulation of the TCR is coupled to B-Raf is unknown.…”

Section: Discussionmentioning

confidence: 99%

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Kidins220/ARMS Associates with B-Raf and the TCR, Promoting Sustained Erk Signaling in T Cells

Deswal

Meyer

Fiala

et al. 2013

The Journal of Immunology

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The activation kinetics of MAPK Erk are critical for T cell development and activation. In particular, sustained Erk signaling is required for T cell activation and effector functions, such as IL-2 production. Although Raf-1 triggers transient Erk activation, B-Raf is implicated in sustained Erk signaling after TCR stimulation. In this study, we show that B-Raf is dephosphorylated on its inhibitory serine 365 upon TCR triggering. However, it is unknown how B-Raf activation is coupled to the TCR. Using mass spectrometry, we identified protein kinase D–interacting substrate of 220 kDa (Kidins220)/ankyrin repeat-rich membrane spanning protein, mammalian target of rapamycin, Rictor, Dock2, and GM130 as novel B-Raf interaction partners. We focused on Kidins220, a protein that has been studied in neuronal cells and found that it associated with the pre-TCR, αβTCR, and γδTCR. Upon prolonged TCR stimulation, the Kidins220–TCR interaction was reduced, as demonstrated by immunoprecipitation and proximity ligation assays. We show that Kidins220 is required for TCR-induced sustained, but not transient, Erk activation. Consequently, induction of the immediate early gene products and transcription factors c-Fos and Erg-1 was blocked, and upregulation of the activation markers CD69, IL-2, and IFN-γ was reduced. Further, Kidins220 was required for optimal calcium signaling. In conclusion, we describe Kidins220 as a novel TCR-interacting protein that couples B-Raf to the TCR. Kidins220 is mandatory for sustained Erk signaling; thus, it is crucial for TCR-mediated T cell activation.

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Section: Discussionmentioning

confidence: 99%

“…TCR-induced activation of Raf-1 leads to a transient Erk signal, whereas activation by B-Raf leads to sustained Erk activation in T cells (20,21). Although sustained Erk signaling is crucial for IL-2 production by T cells (20,22,23), it is not understood how TCR triggering leads to B-Raf activation.…”

mentioning

confidence: 99%

Kidins220/ARMS Associates with B-Raf and the TCR, Promoting Sustained Erk Signaling in T Cells

Deswal

Meyer

Fiala

et al. 2013

The Journal of Immunology

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“…47 Here we show that ADA-deficient T cells fail to phosphorylate ERKs when exposed to dAdo, indicating that ADA-deficient environment in vivo can directly antagonize biochemical events arising from TCR engagement. Because nuclear translocation of phosphorylated ERKs is required for cytokine production and cellcycle progression, [48][49][50] it is conceivable that dAdo-mediated inhibition of ERKs activation was responsible for the suppressed immune functions in ADA Ϫ/Ϫ T cells.…”

Section: Discussionmentioning

confidence: 99%

Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients

Cassani

Mirolo

Cattaneo

et al. 2008

Blood

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Mutations in the adenosine deaminase (ADA) gene are responsible for a form of severe combined immunodeficiency (SCID) caused by the lymphotoxic accumulation of ADA substrates, adenosine and 2-deoxy-adenosine. The molecular mechanisms underlying T-cell dysfunction in humans remain to be elucidated. Here, we show that CD4 ؉ T cells from ADA-SCID patients have severely compromised TCR/CD28-driven proliferation and cytokine production, both at the transcriptional and protein levels. Such an impairment is associated with an intrinsically reduced ZAP-70 phosphorylation, Ca 2؉ flux, and ERK1/2 signaling and to defective transcriptional events linked to CREB and NF-B. Moreover, exposure to 2-deoxy-adenosine results in a stronger inhibition of T-cell activation, mediated by the aberrant A 2A adenosine receptor signaling engagement and PKA hyperactivation, or in a direct apoptotic effect at higher doses. Conversely, in T cells isolated from patients after gene therapy with retrovirally transduced hematopoietic stem/progenitor cells, the biochemical events after TCR triggering occur properly, leading to restored effector functions and normal sensitivity to apoptosis. Overall, our findings provide a better understanding of the pathogenesis of the immune defects associated with an altered purine metabolism and confirm that ADA gene transfer is an efficacious treatment for ADA-SCID. The trials in this study are enrolled at www.ClinicalTrials. gov as #NCT00598481 and #NCT0059978. IntroductionAdenosine deaminase (ADA) is a key enzyme in the purine pathway, ubiquitously expressed, catalyzing the irreversible deamination of adenosine (Ado) and 2Ј-deoxy-adenosine (dAdo). Genetic defects in ADA gene cause an accumulation of purine metabolites in plasma and cells, leading to an inherited form of severe combined immunodeficiency (SCID). 1,2 Accordingly, broad lymphopenia, absence of humoral-and cellular-mediated immunity, recurrent infections, and failure to thrive are the prominent features of the most severe forms of ADA deficiency. 3,4 In addition, the systemic accumulation of purine metabolites can cause alterations in several organs, including the skeleton, lung, liver, gastrointestinal tract, and central nervous system. 4 The clinical phenotypes usually correlate with the severity of genetic mutations, the residual ADA activity and the extent of substrates accumulations. 5 Conflicting data exist on the relative contribution of ADA metabolites in the pathogenesis of the immune dysfunctions. The biochemical hallmarks of ADA deficiency are consistent with the general belief indicating dAdo as the primary cause of lymphotoxicity in ADA-SCID. Exerting its effects at the nucleoside level or after conversion to dATP, accumulation of intracellular dAdo may interfere with deoxynucleotide synthesis and inhibit S-adenosylmethionine-mediated transmethylation reactions, which are required for cell viability and normal differentiation. 6,7 In developing lymphocytes, dAdo has been reported to induce apoptosis through a pathway involving p53 ...

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“…In T cells, upon triggering of the TCR, activation of the MEK/ERK pathway routes signals that are critical for cellular activation, proliferation, and production of cytokines important for the regulation of immune responses (Whitehurst et al, 1992;Karin, 1995;DeSilva et al, 1996;Fields et al, 1996;Li et al, 1996;Alberarola-Ila et al, 1997;Baumgarth et al, 1997). Activation of ERK has been demonstrated to be critical for the proliferation and production of IL-2 in murine primary T cells (Koike et al, 2003). The importance of the JNK cascade in T cell activation and production of IFN-␥ has also been demonstrated (Liu et al, 1997;Yang et al, 1998;Sabapathy et al, 1999;Dong et al, 2000;Behrens et al, 2001).…”

Section: Discussionmentioning

confidence: 97%

Periplocoside E, an Effective Compound fromPeriploca sepiumBge, Inhibited T Cell Activation in Vitro and in Vivo

Zhu¹,

Zhao²,

Yang³

et al. 2005

J Pharmacol Exp Ther

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Periploca sepium Bge, a traditional Chinese herb medicine, is used for treating rheumatoid arthritis in China. Followed the bioactivity-guided isolation, the most potent immunosuppressive compound, periplocoside E (PSE), a pregnane glycoside, had been identified from P. sepium Bge. We investigated the immunosuppressive effects of PSE in vitro and in vivo. The results showed that PSE in a dose-dependent manner significantly inhibited the proliferation of splenocytes induced by concanavalin A and mixed lymphocyte culture reaction at no cytotoxic concentrations (Ͻ5 M). Administration of PSE suppressed a delayed-type hypersensitivity reaction, and ovalbumin (OVA) induced antigen-specific immune responses in mice. In vivo treatment with PSE dose dependently suppressed OVAinduced proliferation and cytokine [interleukin (IL)-2 and interferon (IFN)-␥] production from splenocytes in vitro. Purified T cells from OVA-immunized mice with PSE treatment showed its low ability for activation by OVA plus normal antigen presenting cell stimulation again in vitro. Further studies showed PSE dose dependently inhibited anti-CD3-induced primary T cell proliferation, activation for IL-2R␣ (CD25) expression, and cytokine (IFN-␥ and IL-2) production also at the transcriptional level. PSE was highly specific and significantly inhibited the activation of extracellular signal-regulated kinase and Jun N-terminal kinase, whereas activation of p38 was not affected in T cells stimulated with anti-CD3. These results demonstrated that PSE is an immunosuppressive compound in P. sepium Bge, which directly inhibits T cell activation in vitro and in vivo. This study provided evidence to understand the therapeutic effects of P. sepium Bge and indicated that this herb is appropriate for treatment of T cell-mediated disorders, such as autoimmune diseases.

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A Novel ERK-dependent Signaling Process That Regulates Interleukin-2 Expression in a Late Phase of T Cell Activation

Cited by 72 publications

References 40 publications

Kidins220/ARMS Associates with B-Raf and the TCR, Promoting Sustained Erk Signaling in T Cells

Kidins220/ARMS Associates with B-Raf and the TCR, Promoting Sustained Erk Signaling in T Cells

Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients

Periplocoside E, an Effective Compound fromPeriploca sepiumBge, Inhibited T Cell Activation in Vitro and in Vivo

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