CD25 and CD69 induction by α4β1 outside-in signalling requires TCR early signalling complex proteins

Cimo, Ann Marie; Ahmed, Zamal; McIntyre, Bradley W.; Lewis, Dorothy E.; Ladbury, John E.

doi:10.1042/bj20130485

Cited by 10 publications

(8 citation statements)

References 58 publications

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“…Interestingly, ISDs upregulated CD69 but not CD25, although both require similar stimulation via T-cell receptors [76], [77]. CD25 is required for IL-2-driven proliferation, which suggests that cells treated with ISDs might be less sensitive to the effects of IL-2 than those treated with other diterpenes.…”

Section: Discussionmentioning

confidence: 98%

Dual Role of Novel Ingenol Derivatives from Euphorbia tirucalli in HIV Replication: Inhibition of De Novo Infection and Activation of Viral LTR

et al. 2014

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HIV infection is not cleared by antiretroviral drugs due to the presence of latently infected cells that are not eliminated with current therapies and persist in the blood and organs of infected patients. New compounds to activate these latent reservoirs have been evaluated so that, along with HAART, they can be used to activate latent virus and eliminate the latently infected cells resulting in eradication of viral infection. Here we describe three novel diterpenes isolated from the sap of Euphorbia tirucalli, a tropical shrub. These molecules, identified as ingenols, were modified at carbon 3 and termed ingenol synthetic derivatives (ISD). They activated the HIV-LTR in reporter cell lines and human PBMCs with latent virus in concentrations as low as 10 nM. ISDs were also able to inhibit the replication of HIV-1 subtype B and C in MT-4 cells and human PBMCs at concentrations of EC50 0.02 and 0.09 µM respectively, which are comparable to the EC50 of some antiretroviral currently used in AIDS treatment. Control of viral replication may be caused by downregulation of surface CD4, CCR5 and CXCR4 observed after ISD treatment in vitro. These compounds appear to be less cytotoxic than other diterpenes such as PMA and prostratin, with effective dose versus toxic dose TI>400. Although the mechanisms of action of the three ISDs are primarily attributed to the PKC pathway, downregulation of surface receptors and stimulation of the viral LTR might be differentially modulated by different PKC isoforms.

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Section: Discussionmentioning

confidence: 98%

Dual Role of Novel Ingenol Derivatives from Euphorbia tirucalli in HIV Replication: Inhibition of De Novo Infection and Activation of Viral LTR

et al. 2014

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“…Beyond cell proliferation, ArtinM also promoted the expression of CD25, which is an activation-associated molecule, on CD4 + and CD8 + T cells. Considering that TCR stimulation alone did not induce CD25 expression in naïve CD4 + T cells [ 64 ], we postulate that ArtinM promotes both TCR stimulation and co-stimulation. We previously reported that the interaction of ArtinM with CD3 accounts for the induction of IL-2 and IL-17 production by CD4 + T cells [ 24 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

ArtinM Mediates Murine T Cell Activation and Induces Cell Death in Jurkat Human Leukemic T Cells

Silva

Oliveira-Brito

Gonçalves

et al. 2017

IJMS

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The recognition of cell surface glycans by lectins may be critical for the innate and adaptive immune responses. ArtinM, a d-mannose-binding lectin from Artocarpus heterophyllus, activates antigen-presenting cells by recognizing TLR2 N-glycans and induces Th1 immunity. We recently demonstrated that ArtinM stimulated CD4+ T cells to produce proinflammatory cytokines. Here, we further studied the effects of ArtinM on adaptive immune cells. We showed that ArtinM activates murine CD4+ and CD8+ T cells, augmenting their positivity for CD25, CD69, and CD95 and showed higher interleukin (IL)-2 and interferon (IFN)-γ production. The CD4+ T cells exhibited increased T-bet expression in response to ArtinM, and IL-2 production by CD4+ and CD8+ T cells depended on the recognition of CD3εγ-chain glycans by ArtinM. The ArtinM effect on aberrantly-glycosylated neoplastic lymphocytes was studied in Jurkat T cells, in which ArtinM induced IL-2, IFN-γ, and IL-1β production, but decreased cell viability and growth. A higher frequency of AnnexinV- and propidium iodide-stained cells demonstrated the induction of Jurkat T cells apoptosis by ArtinM, and this apoptotic response was reduced by caspases and protein tyrosine kinase inhibitors. The ArtinM effects on murine T cells corroborated with the immunomodulatory property of lectin, whereas the promotion of Jurkat T cells apoptosis may reflect a potential applicability of ArtinM in novel strategies for treating lymphocytic leukemia.

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“…Interestingly, integrin signaling has been reported to share early TCR signaling molecules (14,15). Therefore, we investigated the effect of big-h3 signaling on the activation of early actors of TCR signaling.…”

Section: Big-h3 Inhibits T-cell Activationmentioning

confidence: 99%

βig-h3 Represses T-Cell Activation in Type 1 Diabetes

et al. 2015

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big-h3/TGF-bi is a secreted protein capable of binding to both extracellular matrix and cells. Human genetic studies recently revealed that in the tgfbi gene encoding for big-h3, three single nucleotide polymorphisms were significantly associated with type 1 diabetes (T1D) risk. Pancreatic islets express big-h3 in physiological conditions, but this expression is reduced in b-cell insult in T1D. Since the integrity of islets is destroyed by autoimmune T lymphocytes, we thought to investigate the impact of big-h3 on T-cell activation. We show here that big-h3 inhibits T-cell activation markers as well as cytotoxic molecule production as granzyme B and IFN-g. Furthermore, big-h3 inhibits early T-cell receptor signaling by repressing the activation of the early kinase protein Lck. Moreover, big-h3-treated T cells are unable to induce T1D upon transfer in Rag2 knockout mice. Our study demonstrates for the first time that T-cell activation is modulated by big-h3, an islet extracellular protein, in order to efficiently avoid autoimmune response.Type 1 diabetes (T1D) is a polygenic autoimmune disease characterized by smoldering inflammatory response directed against the insulin-producing b-islet cells of the pancreas. Both CD4 + and CD8 + T cells are involved in the destruction of b-cells (shed by a prior insult). CD4 + T cells are insulin reactive, and CD8 + T cells play a major role as b-cell killers (1,2). Although both in vitro and in vivo evidence point to a role for regulatory T cells in T-cell-mediated regulation controlling diabetes in mouse models (3), the influence of the inflammatory environment in which they function remains poorly understood. The cross talk between the inflammatory milieu and the immune response during insulitis is likely to be communicated in large part through the extracellular matrix (ECM). big-h3 (also known as TGF-bi) is a secreted protein found in the ECM and it has an N-terminal secretory signal (aa 1-23), four FAS1 homologous internal domains, and a cell attachment site (RGD) at its C terminus (4). big-h3 binds to the ECM through interaction of the YH motif in its FAS1 domains with collagens I, II, IV, and VI (5,6). Its FAS1 domain interacts with its a3b1, aVb3, and aVb5 integrins on the cell surface. Previous studies demonstrated that recombinant big-h3 could preserve the integrity and enhance the function of cultured pancreatic islet cells (7). Conversely, big-h3 knockout (KO) islet function was compromised in vivo after transplantation in recipients with diabetes (8). These studies point out that big-h3 might play an active role in the protection of b-cells against T-cell cytotoxic insult in T1D. The effect of big-h3 on T-cell function and activation relative to its roles in islet b-cell-ECM destruction in T1D in mice has never been investigated and it is the focus of our project. RESEARCH DESIGN AND METHODS MiceFemale C57Bl/6 NOD mice were bred and housed in specific pathogen-free conditions. T1D was chemically induced inC57Bl/6 using a standard low-dose (35 mg/kg) streptozotoci...

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CD25 and CD69 induction by α4β1 outside-in signalling requires TCR early signalling complex proteins

Cited by 10 publications

References 58 publications

Dual Role of Novel Ingenol Derivatives from Euphorbia tirucalli in HIV Replication: Inhibition of De Novo Infection and Activation of Viral LTR

Dual Role of Novel Ingenol Derivatives from Euphorbia tirucalli in HIV Replication: Inhibition of De Novo Infection and Activation of Viral LTR

ArtinM Mediates Murine T Cell Activation and Induces Cell Death in Jurkat Human Leukemic T Cells

βig-h3 Represses T-Cell Activation in Type 1 Diabetes

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