Receptor signaling in immune cell development and function

Zhong, Xiao‐Ping; Shin, Jin‐Wook; Gorentla, Balachandra K.; O'Brien, Tommy; Srivatsan, Sruti; Xu, Li; Chen, Yong; Xie, Denghui; Pan, Hongjie

doi:10.1007/s12026-010-8175-9

Cited by 28 publications

(26 citation statements)

References 151 publications

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“…PLCG1 function is critical in several cell types, but within the hematopoietic system, it is necessary in T and NK cells, whereas PLCG2 is important in mast, NK, and B cells and in platelets. 36,41 PLCG1 is activated in T cells downstream of TCR/CD3 activation, triggering the activation of key lymphomagenesis pathways such as RAS/RAF/extracellular signalregulated kinase, protein kinase C/NFkB pathways by DAG, or calmodulin/calcineurin/NFAT by IP3/Ca 21 . To date, mutations have been described only sporadically in this gene (48 mutations found in 5892 analyzed cases, according to the Catalogue of Somatic Mutations in Cancer database).…”

Section: Discussionmentioning

confidence: 99%

“…The protein encoded by the PLCG1 gene plays a central role in the intricate network of downstream signaling elicited by TCR (reviewed in Zhong et al 36 ). Activated PLCG1 catalyzes the formation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate.…”

Section: Expression Of Plcg1 Downstream Targets In Patients With Plcgmentioning

confidence: 99%

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PLCG1 mutations in cutaneous T-cell lymphomas

Vaqué

Gómez‐López

Monsálvez

et al. 2014

Blood

200

199

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Key Points• Activating mutations in PLCG1 are a frequent finding in tumoral CTCL samples. This raises the possibility of targeted therapies against PLCG1 signaling pathway, using calcineurin inhibitors.Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of primary cutaneous T-cell lymphoproliferative processes, mainly composed of mycosis fungoides and Sézary syndrome, the aggressive forms of which lack an effective treatment. The molecular pathogenesis of CTCL is largely unknown, although neoplastic cells show increased signaling from T-cell receptors (TCRs). DNAs from 11 patients with CTCL, both normal and tumoral, were target-enriched and sequenced by massive parallel sequencing for a selection of 524 TCR-signaling-related genes. Identified variants were validated by capillary sequencing. Multiple mutations were found that affected several signaling pathways, such as TCRs, nuclear factor kB, or Janus kinase/signal transducer and activator of transcription, but PLCG1 was found to be mutated in 3 samples, 2 of which featured a redundant mutation (c.1034T>C, S345F) in exon 11 that affects the PLCx protein catalytic domain. This mutation was further analyzed by quantitative polymerase chain reaction genotyping in a new cohort of 42 patients with CTCL, where it was found in 19% of samples. Immunohistochemical analysis for nuclear factor of activated T cells (NFAT) showed that PLCG1-mutated cases exhibited strong NFAT nuclear immunostaining. Functional studies demonstrated that PLCG1 mutants elicited increased downstream signaling toward NFAT activation, and inhibition of this pathway resulted in reduced CTCL cell proliferation and cell viability. Thus, increased proliferative and survival mechanisms in CTCL may partially depend on the acquisition of somatic mutations in PLCG1 and other genes that are essential for normal T-cell differentiation. (Blood. 2014;123(13):2034-2043

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Section: Discussionmentioning

confidence: 99%

Section: Expression Of Plcg1 Downstream Targets In Patients With Plcgmentioning

confidence: 99%

PLCG1 mutations in cutaneous T-cell lymphomas

Vaqué

Gómez‐López

Monsálvez

et al. 2014

Blood

200

199

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“…The rictor-containing mTORC2 phosphorylates both Akt at serine 473 residue to promote Akt activation and cell survival and PKCθ to promote T-helper (Th)2 differentiation (9,10). Engagement of the TCR activates both mTORC1 and mTORC2, which is dependent on the RasGRP1-Ras-Erk1/2 pathway and is inhibited by diacylglycerol kinases (11)(12)(13). Rapamycin treatment or genetic ablation of mTOR induces T-cell anergy and inhibits helper T-cell differentiation but promotes expansion of natural regulatory T cells (nTregs) and the generation of inducible Tregs (9,(14)(15)(16).…”

Section: T-cell Activation | Signal Transductionmentioning

confidence: 99%

Tumor suppressor TSC1 is critical for T-cell anergy

Xie

Lou

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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T-cell anergy is a state of T cells that is hyporesponsive to stimulation via the T-cell receptor and costimulatory molecules and is thought to be important for self-tolerance. How T-cell anergy is regulated is still poorly understood. We report here that tuberous sclerosis (TSC)1 is critical for T-cell anergy. Deficiency of TSC1 resulted in enhanced Tcell proliferation and cytokine production in the absence of cluster of differentiation (CD)28-mediated costimulation, accompanied by enhanced T-cell metabolism. Resistance of TSC1-deficient T cells to anergy is correlated with increased signaling through the mammalian target of rapamycin complex (mTORC)1 and can be reverted by treatment of these cells with mTORC1 inhibitor rapamycin. Expression of the inducible costimulator (ICOS) is increased in TSC1-deficient T cells, which can be inhibited by rapamycin. Simultaneous blockade of both CD28 and ICOS costimulation partially restored sensitivity of TSC1-deficient T cells to anergy induction. Together, our data indicate that TSC1 is crucial for T-cell anergy by inhibiting mTORC1 signaling through both ICOS-dependent and -independent mechanisms.T-cell activation | signal transduction C oordinated signals from the T-cell receptor (TCR), costimulatory receptors, and cytokine receptors ensure naïve T-cell activation and differentiation to proper effector T cells. T cells can be made anergic by stimulation through their TCR without a costimulatory signal, by stimulation with partial agonist peptides in the presence of costimulation, or by treatment with the Ca 2+ ionophore ionomycin (1-3). Anergic T cells do not respond to antigen restimulation even in the presence of appropriate costimulation. They are impaired in producing cytokines such as IFN-γ or IL-2, defective in proliferative response, and metabolically inert (4-7). T-cell anergy is thought to be important for preventing self-reactive T cells from full activation to trigger autoimmune diseases.The mammalian target of rapamycin (mTOR) integrates numerous environmental stimuli including growth factors, nutrients, and stress-activated signals to regulate cell metabolism, survival, growth, and proliferation (8). mTOR associates with multiple proteins and forms two distinct signaling complexes. mTOR complex (mTORC)1 contains raptor and phosphorylates ribosomal protein s6 kinase, 70-kd, 1 (S6K1) and eukaryotic translation initiation factor 4e-binding protein 1 (4E-BP1) to promote ribosomogenesis and protein translation. The rictor-containing mTORC2 phosphorylates both Akt at serine 473 residue to promote Akt activation and cell survival and PKCθ to promote T-helper (Th)2 differentiation (9, 10). Engagement of the TCR activates both mTORC1 and mTORC2, which is dependent on the RasGRP1-Ras-Erk1/2 pathway and is inhibited by diacylglycerol kinases (11-13). Rapamycin treatment or genetic ablation of mTOR induces T-cell anergy and inhibits helper T-cell differentiation but promotes expansion of natural regulatory T cells (nTregs) and the generation of inducible Tregs (9, 14-...

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“…42 mTOR promotes effector T-cell differentiation, controls T-cell trafficking, inhibits generation of inducible regulatory T cells, and down-regulates memory T-cell responses. 43,44 Tight control of mTOR signaling is critical for maintaining normal T-cell homeostasis. 45 Both positive and negative roles of mTOR signaling have also been reported in TLR-induced responses in dendritic cells and macrophages.…”

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confidence: 99%

Regulation of mast cell survival and function by tuberous sclerosis complex 1

Shin

Pan²,

Zhong

2012

Blood

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Mast cells play critical roles in allergic disorders and asthma. The importance of tuberous sclerosis complex 1/2-mammalian target of rapamycin (TSC1/2-mTOR) signaling in mast cells is unknown. Here, we report that TSC1 is a critical regulator for mTOR signaling in mast cells downstream of FcRI and c-Kit, and differentially controls mast cell degranulation and cytokine production. TSC1-deficiency results in impaired mast cell degranulation, but enhanced cytokine production in vitro and in vivo after FcRI engagement. Furthermore, TSC1 is critical for mast cell survival through multiple pathways of apoptosis including the downregulation of p53, miR-34a, reactive oxygen species, and the up-regulation of Bcl-2. Together, these findings reveal that TSC1 is a critical regulator of mast cell activation and survival, suggesting the manipulation of the TSC1/2-mTOR pathway as a therapeutic strategy for mast cell-mediated diseases. IntroductionMast cells play pivotal roles in chronic allergic inflammation and acute anaphylaxis, which are largely mediated by the high-affinity immunoglobulin E (IgE) receptor (FcεRI) on their surface. Crosslinking of IgE-bound FcεRI by cognate antigen (Ag) initiates multiple signal transduction pathways that trigger the release of proinflammatory mediators, such as histamine from granules and de novo synthesis and secretion of cytokines. [1][2][3] FcεRI engagement activates the Src-family protein tyrosine kinases (PTK) Lyn, which phosphorylates immunoreceptor tyrosine-based activation motifs (ITAMs) of the ␤ and ␥-subunits of FcεRI and subsequently activates Syk. 4 These events are followed by recruiting and activating downstream effector and adaptor molecules, such as linker for activated T cells (LAT), 5 SH2 domain-containing leukocyte phosphoprotein of 76 kDa, 6 Rac GTPase guanine nucleotide exchange factor Vav1, 7 Tec family kinase Bruton tyrosine kinase, 8 and phospholipase C␥ (PLC␥). 9 In addition to Lyn, another Src PTK, Fyn, induces activation of Grb2-associated binder 2 without requirement of Lyn and LAT to promote phosphatidylinositol 3-kinase (PI3K) activation. [10][11][12][13] In turn, these signals are transmitted to downstream signaling molecules including PKCs and MAPKs that are important for mast cell activation. [14][15][16][17] The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase linked with the PI3K pathway via Akt. 18 mTOR senses both environmental and intracellular stimuli such as growth factors, nutrients, energy, and stress, and is capable of integrating diverse biologic processes including cell metabolism, growth, autophagy, and survival. 18,19 mTOR forms 2 functionally and structurally distinct complexes: rapamycinsensitive mTOR complex 1 (mTORC1) and rapamycin-insensitive mTORC2. 19 mTORC1 phosphorylates ribosomal S6 kinases (S6Ks) and eIF4E-binding proteins (4E-BPs) to promote ribosomogenesis and cap-dependent translation. 18 mTORC2 directly phosphorylates Akt at Ser473 to promote Akt activation, and is also necessary to p...

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Receptor signaling in immune cell development and function

Cited by 28 publications

References 151 publications

PLCG1 mutations in cutaneous T-cell lymphomas

PLCG1 mutations in cutaneous T-cell lymphomas

Tumor suppressor TSC1 is critical for T-cell anergy

Regulation of mast cell survival and function by tuberous sclerosis complex 1

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