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Craig B Thompson - One of the best experts on this subject based on the ideXlab platform.
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revving the engine signal transduction fuels t Cell Activation
Immunity, 2007Co-Authors: Russell G Jones, Craig B ThompsonAbstract:For initiation of an immune response, resting T Cells must reprogram their metabolism. Continuing the "From the Field" series (see Editorial [2007] 26, 131), Jones and Thompson draw attention to the importance of metabolism during T Cell Activation and consider how this process is regulated by receptor-mediated signal transduction.
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ctla 4 and pd 1 receptors inhibit t Cell Activation by distinct mechanisms
Molecular and Cellular Biology, 2005Co-Authors: Richard V Parry, Craig B Thompson, Jens M Chemnitz, Kenneth A Frauwirth, Anthony R Lanfranco, Inbal Braunstein, Sumire V Kobayashi, Peter S Linsley, James L RileyAbstract:CTLA-4 and PD-1 are receptors that negatively regulate T-Cell Activation. Ligation of both CTLA-4 and PD-1 blocked CD3/CD28-mediated upregulation of glucose metabolism and Akt activity, but each accomplished this regulation using separate mechanisms. CTLA-4-mediated inhibition of Akt phosphorylation is sensitive to okadaic acid, providing direct evidence that PP2A plays a prominent role in mediating CTLA-4 suppression of T-Cell Activation. In contrast, PD-1 signaling inhibits Akt phosphorylation by preventing CD28-mediated Activation of phosphatidylinositol 3-kinase (PI3K). The ability of PD-1 to suppress PI3K/AKT Activation was dependent upon the immunoreceptor tyrosine-based switch motif located in its cytoplasmic tail, adding further importance to this domain in mediating PD-1 signal transduction. Lastly, PD-1 ligation is more effective in suppressing CD3/CD28-induced changes in the T-Cell transcriptional profile, suggesting that differential regulation of PI3K Activation by PD-1 and CTLA-4 ligation results in distinct Cellular phenotypes. Together, these data suggest that CTLA-4 and PD-1 inhibit T-Cell Activation through distinct and potentially synergistic mechanisms.
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ctla 4 can function as a negative regulator of t Cell Activation
Immunity, 1994Co-Authors: Theresa L Walunas, Gordon J. Freeman, Christina Y Bakker, Craig B Thompson, Deborah J Lenschow, Jonathan Green, Jeffrey A BluestoneAbstract:CD28 and CTLA-4 are related glycoproteins found on T Cells. Ligation of CD28 following antigen receptor engagement provides a costimulatory signal required for T Cell Activation. Anti-CTLA-4 antibodies were generated to examine the role of the CTLA-4 receptor on murine T Cells. Expression of CTLA-4 as a homodimer is up-regulated 2-3 days following T Cell Activation. Anti-CTLA-4 antibodies and Fab fragments augmented T Cell proliferation in an allogeneic MLR. However, when optimal costimulation and Fc cross-linking were present, anti-CTLA-4 Mabs inhibited T Cell proliferation. Together, these results suggest that the MAb may obstruct the interaction of CTLA-4 with its natural ligand and block a negative signal, or directly signal T Cells to down-regulate immune function.
Chen Dong - One of the best experts on this subject based on the ideXlab platform.
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a butyrophilin family member critically inhibits t Cell Activation
Journal of Immunology, 2010Co-Authors: Tomohide Yamazaki, Inigo Goya, Daniel Graf, Suzanne Craig, Natalia Martinorozco, Chen DongAbstract:The costimulatory molecules in the B7-CD28 families are important in the regulation of T Cell Activation and tolerance. The butyrophilin family of proteins shares sequence and structure homology with B7 family molecules; however, the function of the butyrophilin family in the immune system has not been defined. In this study, we performed an analysis on multiple butyrophilin molecules and found that butyrophilin-like (BTNL)1 molecule functions to dampen T Cell Activation. BTNL1 mRNA was broadly expressed, but its protein was only found in APCs and not T Cells. The putative receptor for BTNL1 was found on activated T Cells and APCs. Also, recombinant BTNL1 molecule inhibited T Cell proliferation by arresting Cell cycle progression. The administration of neutralizing Abs against BTNL1 provoked enhanced T Cell Activation and exacerbated disease in autoimmune and asthma mouse models. Therefore, BTNL1 is a critical inhibitory molecule for T Cell Activation and immune diseases.
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b7s1 a novel b7 family member that negatively regulates t Cell Activation
Immunity, 2003Co-Authors: Durbaka V R Prasad, Sabrina Richards, Xoi Muoi Mai, Chen DongAbstract:T Cell Activation by antigen-presenting Cells (APC) is regulated by positive and negative costimulatory molecules in the B7 family. Here we describe a novel addition in this family, designated as B7S1, which is uniquely anchored to the Cell membrane via a GPI linkage. B7S1 is expressed on professional APC and widely distributed in nonlymphoid tissues. A soluble B7S1-Ig fusion protein binds to activated but not naive T Cells. B7S1-Ig inhibits T Cell Activation and IL-2 production. A monoclonal antibody that blocks binding of B7S1 to its receptor enhances T Cell proliferation in vitro and exacerbates experimental autoimmune encephalomyelitis in vivo. This study identifies a novel negative regulator of T Cell Activation and further reveals complex costimulatory regulation of immune responses.
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icos co stimulatory receptor is essential for t Cell Activation and function
Nature, 2001Co-Authors: Chen Dong, Amy E Juedes, Ulla Angela Temann, Sujan Shresta, James P Allison, Nancy H Ruddle, Richard A FlavellAbstract:T-lymphocyte Activation and immune function are regulated by co-stimulatory molecules. CD28, a receptor for B7 gene products, has a chief role in initiating T-Cell immune responses1,2. CTLA4, which binds B7 with a higher affinity, is induced after T-Cell Activation and is involved in downregulating T-Cell responses3,4. The inducible co-stimulatory molecule (ICOS), a third member of the CD28/CTLA4 family, is expressed on activated T Cells5,6. Its ligand B7H/B7RP-1 is expressed on B Cells and in non-immune tissues after injection of lipopolysaccharide into animals6,7. To understand the role of ICOS in T-Cell Activation and function, we generated and analysed ICOS-deficient mice. Here we show that T-Cell Activation and proliferation are defective in the absence of ICOS. In addition, ICOS-/- T Cells fail to produce interleukin-4 when differentiated in vitro or when primed in vivo. ICOS is required for humoral immune responses after immunization with several antigens. ICOS-/- mice showed greatly enhanced susceptibility to experimental autoimmune encephalomyelitis, indicating that ICOS has a protective role in inflammatory autoimmune diseases.
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jnk is required for effector t Cell function but not for t Cell Activation
Nature, 2000Co-Authors: Chen Dong, Derek D Yang, Cathy Tournier, Alan J Whitmarsh, Roger J Davis, Richard A FlavellAbstract:The hallmark of T-Cell Activation is the production of interleukin 2 (IL-2). c-Jun amino-terminal kinase (JNK), a MAP kinase that phosphorylates c-Jun and other components of the AP-1 group of transcription factors, has been implicated in the Activation of IL-2 expression. Previously, we found that T Cells from mice deficient in the Jnk1 or Jnk2 gene can be activated and produce IL-2 normally, but are deficient in functional differentiation into Th1 or Th2 subsets. However, studies of mice with compound mutations indicate that JNK1 and JNK2 are redundant during mouse development. Here we use three new mouse models in which peripheral T Cells completely lack JNK proteins or signalling, to test whether the JNK signalling pathway is crucial for IL-2 expression and T-Cell Activation. Unexpectedly, these T Cells made more IL-2 and proliferated better than wild-type Cells. However, production of effector T-Cell cytokines did require JNK. Thus, JNK is necessary for T-Cell differentiation but not for naive T-Cell Activation.
Cem Akin - One of the best experts on this subject based on the ideXlab platform.
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Mast Cell Activation syndromes.
The Journal of allergy and clinical immunology, 2017Co-Authors: Cem AkinAbstract:Mast Cell Activation is common and possibly necessary for maintenance of survival. Disordered mast Cell Activation occurs when mast Cells are pathologically overproduced or if their Activation is out of proportion to the perceived threat to homeostasis. Mast Cell Activation syndrome refers to a group of disorders with diverse causes presenting with episodic multisystem symptoms as the result of mast Cell mediator release. Despite introduction of diagnostic criteria and some advances in treatment in the last decade, many areas of mast Cell Activation syndrome are in need of research. This article reviews our current knowledge about the various types of mast Cell Activation disorders, their treatment, and areas of uncertainty in need of future investigation.
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mast Cell Activation syndrome proposed diagnostic criteria
The Journal of Allergy and Clinical Immunology, 2010Co-Authors: Cem Akin, Peter Valent, Dean D MetcalfeAbstract:The term mast Cell Activation syndrome (MCAS) is finding increasing use as a diagnosis for subjects who present with signs and symptoms involving the dermis, gastrointestinal track, and cardiovascular system frequently accompanied by neurologic complaints. Such patients often have undergone multiple extensive medical evaluations by different physicians in varied disciplines without a definitive medical diagnosis until the diagnosis of MCAS is applied. However, MCAS as a distinct clinical entity has not been generally accepted, nor do there exist definitive criteria for diagnosis. Based on current understanding of this disease "syndrome" and on what we do know about mast Cell Activation and resulting pathology, we will explore and propose criteria for its diagnosis. The proposed criteria will be discussed in the context of other disorders involving mast Cells or with similar presentations and as a basis for further scientific study and validation.
Seumas Mccroskery - One of the best experts on this subject based on the ideXlab platform.
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myostatin negatively regulates satellite Cell Activation and self renewal
Journal of Cell Biology, 2003Co-Authors: Seumas Mccroskery, Linda Maxwell, Mark Thomas, Mridula Sharma, Ravi KambadurAbstract:Satellite Cells are quiescent muscle stem Cells that promote postnatal muscle growth and repair. Here we show that myostatin, a TGF-β member, signals satellite Cell quiescence and also negatively regulates satellite Cell self-renewal. BrdU labeling in vivo revealed that, among the Myostatin-deficient satellite Cells, higher numbers of satellite Cells are activated as compared with wild type. In contrast, addition of Myostatin to myofiber explant cultures inhibits satellite Cell Activation. Cell cycle analysis confirms that Myostatin up-regulated p21, a Cdk inhibitor, and decreased the levels and activity of Cdk2 protein in satellite Cells. Hence, Myostatin negatively regulates the G1 to S progression and thus maintains the quiescent status of satellite Cells. Immunohistochemical analysis with CD34 antibodies indicates that there is an increased number of satellite Cells per unit length of freshly isolated Mstn−/− muscle fibers. Determination of proliferation rate suggests that this elevation in satellite Cell number could be due to increased self-renewal and delayed expression of the differentiation gene (myogenin) in Mstn−/− adult myoblasts. Taken together, these results suggest that Myostatin is a potent negative regulator of satellite Cell Activation and thus signals the quiescence of satellite Cells.
Christine N Metz - One of the best experts on this subject based on the ideXlab platform.
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cholinergic stimulation blocks endothelial Cell Activation and leukocyte recruitment during inflammation
Journal of Experimental Medicine, 2005Co-Authors: Rubina W Saeed, Kevin J. Tracey, Jared M. Huston, Santosh Varma, Tina Pengnemeroff, Barbara Sherry, David Balakhaneh, Yousef Alabed, Christine N MetzAbstract:Endothelial Cell Activation plays a critical role in regulating leukocyte recruitment during inflammation and infection. Based on recent studies showing that acetylcholine and other cholinergic mediators suppress the production of proinflammatory cytokines via the α7 nicotinic acetylcholine receptor (α7 nAChR) expressed by macrophages and our observations that human microvascular endothelial Cells express the α7 nAChR, we examined the effect of cholinergic stimulation on endothelial Cell Activation in vitro and in vivo. Using the Shwartzman reaction, we observed that nicotine (2 mg/kg) and the novel cholinergic agent CAP55 (12 mg/kg) inhibit endothelial Cell adhesion molecule expression. Using endothelial Cell cultures, we observed the direct inhibitory effects of acetylcholine and cholinergic agents on tumor necrosis factor (TNF)-induced endothelial Cell Activation. Mecamylamine, an nAChR antagonist, reversed the inhibition of endothelial Cell Activation by both cholinergic agonists, confirming the antiinflammatory role of the nAChR cholinergic pathway. In vitro mechanistic studies revealed that nicotine blocked TNF-induced nuclear factor–κB nuclear entry in an inhibitor κB (IκB)α- and IκBe-dependent manner. Finally, with the carrageenan air pouch model, both vagus nerve stimulation and cholinergic agonists significantly blocked leukocyte migration in vivo. These findings identify the endothelium, a key regulator of leukocyte trafficking during inflammation, as a target of anti-inflammatory cholinergic mediators.
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ethanol blocks leukocyte recruitment and endothelial Cell Activation in vivo and in vitro
Journal of Immunology, 2004Co-Authors: Rubina W Saeed, Kevin J. Tracey, Santosh Varma, Barbara Sherry, Tina Peng, Christine N MetzAbstract:Immune system impairment and increased susceptibility to infection among alcohol abusers is a significant but not well-understood problem. We hypothesized that acute ethanol administration would inhibit leukocyte recruitment and endothelial Cell Activation during inflammation and infection. Using LPS and carrageenan air pouch models in mice, we found that physiological concentrations of ethanol (1-5 g/kg) significantly blocked leukocyte recruitment (50-90%). Because endothelial Cell Activation and immune Cell-endothelial Cell interactions are critical regulators of leukocyte recruitment, we analyzed the effect of acute ethanol exposure on endothelial Cell Activation in vivo using the localized Shwartzman reaction model. In this model, ethanol markedly suppressed leukocyte accumulation and endothelial Cell adhesion molecule expression in a dose-dependent manner. Finally, we examined the direct effects of ethanol on endothelial Cell Activation and leukocyte-endothelial Cell interactions in vitro. Ethanol, at concentrations within the range found in human blood after acute exposure and below the levels that induce cytotoxicity (0.1-0.5%), did not induce endothelial Cell Activation, but significantly inhibited TNF-mediated endothelial Cell Activation, as measured by adhesion molecule (E-selectin, ICAM-1, VCAM-1) expression and chemokine (IL-8, MCP-1, RANTES) production and leukocyte adhesion in vitro. Studies exploring the potential mechanism by which ethanol suppresses endothelial Cell Activation revealed that ethanol blocked NF-kappaB nuclear entry in an IkappaBalpha-dependent manner. These findings support the hypothesis that acute ethanol overexposure may increase the risk of infection and inhibit the host inflammatory response, in part, by blocking endothelial Cell Activation and subsequent immune Cell-endothelial Cell interactions required for efficient immune Cell recruitment.