Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thymic plasmacytoid dendritic cells (pDCs) are located predominantly in the medulla and at the corticomedullary junction, the entry site of bone marrow-derived multipotential precursor cells into the thymus, allowing for interactions between thymic pDCs and precursor cells. We demonstrate that in vitro-generated pDCs stimulated with CpG or virus impaired the development of human autologous CD34(+)CD1a(-) thymic progenitor cells into the T-cell lineage. Rescue by addition of neutralizing type I interferon (IFN) antibodies strongly implies that endogenously produced IFN-alpha/beta is responsible for this inhibitory effect. Consistent with this notion, we show that exogenously added IFN-alpha had a similar impact on IL-7- and Notch ligand-induced development of thymic CD34(+)CD1a(-) progenitor cells into T cells, because induction of CD1a, CD4, CD8, and TCR/CD3 surface expression and rearrangements of TCRbeta V-DJ gene segments were severely impaired. In addition, IL-7-induced proliferation but not survival of the developing thymic progenitor cells was strongly inhibited by IFN-alpha. It is evident from our data that IFN-alpha inhibits the IL-7R signal transduction pathway, although this could not be attributed to interference with either IL-7R proximal (STAT5, Akt/PKB, Erk1/2) or distal (p27(kip1), pRb) events.
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PMID:Stimulated plasmacytoid dendritic cells impair human T-cell development. 1691 11

The TEL-JAK2 gene fusion, which has been identified in human leukemia, encodes a chimeric protein endowed with constitutive tyrosine kinase activity. TEL-JAK2 transgenic expression in the mouse lymphoid lineage results in fatal and rapid T-cell leukemia/lymphoma. In the present report we show that T-cell leukemic cells from EmuSRalpha-TEL-JAK2 transgenic mice present an aberrant CD8(+) differentiation phenotype, as determined by the expression of stage-specific cell surface markers and lineage-specific genes. TEL-JAK2 transforms immature CD4(-)CD8(-) double-negative thymocytes, as demonstrated by the development of T-cell leukemia with full penetrance in a Rag2-deficient genetic background. This disease is similar to the bona fide TEL-JAK2 disease as assessed by phenotypic and gene profiling analyses. Pre-TCR signaling synergizes with TEL-JAK2 to transform immature thymocytes and initiate leukemogenesis as shown by (1) the delayed leukemia onset in Rag2-, CD3epsilon- and pTalpha-deficient mice, (2) the occurrence of recurrent chromosomal alterations in pre-TCR-deficient leukemia, and (3) the correction of delayed leukemia onset in Rag2-deficient TEL-JAK2 mice by an H-Y TCRalphabeta transgene that mimics pre-TCR signaling. Although not affecting leukemia incidence and mouse survival, TCRalphabeta expression was shown to facilitate leukemic cell expansion in secondary lymphoid organs.
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PMID:Pre-TCR expression cooperates with TEL-JAK2 to transform immature thymocytes and induce T-cell leukemia. 1719 90

Expression of the CD8 alpha alpha homodimer has been used to differentiate lymphoid (CD8alpha(+)) from myeloid (CD8alpha(-)) dendritic cells (DCs). We have reported that CD8alpha(+) and CD8alpha(-) DCs have differential abilities to stimulate proliferation in allogeneic T cells. However, no specific function has been attributed to DC-derived CD8alpha. The current study examines the hypothesis that CD8 alpha alpha expression on DCs regulates DC-induced T cell activation. CD8alpha(-) transduced bone marrow-derived DCs were more potent stimulators of T cell proliferation, and produced significantly greater quantities of IL-12 in co-culture with T cells. LCK, a kinase whose expression is reported to be T cell-restricted and known to bind to the cytoplasmic tail of CD8 alpha beta in T cells, was detected readily in primary CD8alpha(+) splenic DCs and at greater levels than CD8alpha(-) DCs from the same tissues. LCK also co-precipitated with CD8alpha on immunblots strongly suggesting its role in CD8alpha(+) DC-induced T cell activation. Collectively, these data show that CD8alpha expressed on DC may not only be a lineage/maturation marker but also contribute to DC function.
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PMID:Dendritic cell-T cell interactions: CD8 alpha alpha expressed on dendritic cells regulates T cell proliferation. 1722 89

Recent data from three laboratories have identified the TEC kinases, ITK and RLK, as crucial regulators of CD8(+) T-cell development into the conventional lymphocyte lineage. In the absence of ITK and RLK, CD4(+)CD8(+) thymocytes upregulate the T-box transcription factor eomesodermin, and develop into mature CD8(+) T cells that resemble memory cells, exhibit immediate effector cytokine production and depend on IL-15. Furthermore, the selection of these non-conventional 'innate' T cells results from interactions with haematopoietic cells in the thymus. These findings lead to the hypothesis that altered TCR signalling, together with distinct co-stimulatory signals, is the basis for the development of non-conventional T-cell lineages.
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PMID:Signalling through TEC kinases regulates conventional versus innate CD8(+) T-cell development. 1747 28

In the BCR/ABL DA1-3b mouse model of acute myelogenous leukemia, dormant tumor cells may persist in the host in a state of equilibrium with the CD8(+) CTL-mediated immune response by actively inhibiting T cells. Dormant tumor cells also show a progressive decrease of suppressor of cytokine signaling 1 (SOCS1) gene expression and a deregulation of the Janus-activated kinase/signal transducers and activators of transcription (JAK/STAT) pathway due to methylation of the SOCS1 gene. Dormant tumor cells were more resistant to apoptosis induced by specific CTLs, but resistance decreased when SOCS1 expression was restored via demethylation or gene transfer. AG490 JAK2 inhibitor decreased the resistance of dormant tumor cells to CTLs, but MG132 proteasome inhibitor was effective only in SOCS1-transfected cells. Thus, SOCS1 regulation of the JAK/STAT pathways contributes to the resistance of tumor cells to CTL-mediated killing. Resistance of dormant tumor cells to apoptosis was also observed when induced by irradiation, cytarabine, or imatinib mesylate, but was reduced by SOCS1 gene transfer. This cross-resistance to apoptosis was induced by interleukin 3 (IL-3) overproduction by dormant tumor cells and was reversed with an anti-IL-3 antibody. Thus, tumor cells that remain dormant for long periods in the host in spite of a specific CTL immune response may deregulate their JAK/STAT pathways and develop cross-resistance to various treatments through an IL-3 autocrine loop. These data suggest possible new therapeutic targets to eradicate dormant tumor cells.
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PMID:Dormant tumor cells develop cross-resistance to apoptosis induced by CTLs or imatinib mesylate via methylation of suppressor of cytokine signaling 1. 1748 65

Induction of a chronic eczema is a most efficient therapy for alopecia areata (AA). We had noted a reduction in regulatory T cells during AA induction and wondered whether regulatory T cells may become recruited or expanded during repeated skin sensitization or whether additional regulatory cells account for hair regrowth. AA could not be cured by the transfer of CD4(+)CD25(high) lymph node cells from mice repeatedly treated with a contact sensitizer. This obviously is a consequence of a dominance of freshly activated cells as compared with regulatory CD4(+)CD25(+) T cells. Instead, a population of Gr-1(+)CD11b(+) cells was significantly increased in skin and spleen of AA mice repeatedly treated with a contact sensitizer. Gr-1(+)CD11b(+) spleen cells mostly expressed CD31. Expression of several proinflammatory cytokines as well as of the IFN-gamma receptor and the TNF receptor I were increased. Particularly in the skin, Gr-1(+) cells expressed several chemokines and CCR8 at high levels. Gr-1(+)CD11b(+) cells most potently suppressed AA effector cell proliferation in vitro and promoted partial hair regrowth in vivo. When cocultured with CD4(+) or CD8(+) cells from AA mice, the Gr-1(+)CD11b(+) cells secreted high levels of NO. However, possibly due to high level Bcl-2 protein expression in AA T cells, apoptosis induction remained unaltered. Instead, zeta-chain expression was strongly down-regulated, which was accompanied by a decrease in ZAP70 and ERK1/2 phosphorylation. Thus, a chronic eczema supports the expansion and activation of myeloid suppressor cells that, via zeta-chain down-regulation, contribute to autoreactive T cell silencing in vitro and in vivo.
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PMID:The importance of myeloid-derived suppressor cells in the regulation of autoimmune effector cells by a chronic contact eczema. 1791 92

CD8(+) tumor-infiltrating lymphocytes (TIL) lack in vivo and in vitro lytic function due to a signaling deficit characterized by failure to flux calcium or activate tyrosine kinase activity upon contact with cognate tumor cells. Although CD3 zeta is phosphorylated by conjugation in vitro with cognate tumor cells, showing that TIL are triggered, PLC gamma-1, LAT, and ZAP70 are not activated and LFA-1 is not affinity-matured, and because p56(lck) is required for LFA-1 activation, this implies that the signaling blockade is very proximal. Here, we show that TIL signaling defects are transient, being reversed upon purification and brief culture in vitro, implying a fast-acting "switch". Biochemical analysis of purified nonlytic TIL shows that contact with tumor cells causes transient activation of p56(lck) ( approximately 10 s) which is rapidly inactivated. In contrast, tumor-induced activation of p56(lck) in lytic TIL is sustained coincident with downstream TCR signaling and lytic function. Shp-1 is robustly active in nonlytic TIL compared with lytic TIL, colocalizes with p56(lck) in nonlytic TIL, and inhibition of Shp-1 activity in lytic TIL in vitro blocks tumor-induced defective TIL cytolysis. Collectively, our data support the notion that contact of nonlytic TIL with tumor cells, and not with tumor-infiltrating myeloid-derived suppressor cells, causes activation of Shp-1 that rapidly dephosphorylates the p56(lck) activation motif (Y394), thus inhibiting effector phase functions.
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PMID:Suppression of proximal T cell receptor signaling and lytic function in CD8+ tumor-infiltrating T cells. 1805 73

The relationship between bile duct damage and portal fibrosis in chronic liver diseases remains unclear. This study was designed to show whether human intrahepatic biliary epithelial cells can undergo epithelial-mesenchymal cell transition, thereby directly contributing to fibrogenesis. Primary human cholangiocytes were stimulated with transforming growth factor-beta (TGFbeta) or TGFbeta-presenting T cells and examined for evidence of transition to a mesenchymal phenotype. Liver sections were labelled to detect antigens associated with biliary epithelial cells (cytokeratin 7 and 19 and E-cadherin), T cells (CD8), epithelial-mesenchymal transition (S100A4, vimentin and matrix metalloproteinase-2 (MMP-2)), myofibroblasts (alpha-smooth muscle actin) and intracellular signal-transduction mediated by phosphorylated (p)Smad 2/3; in situ hybridisation was performed to detect mRNA encoding TGFbeta and S100A4. Stimulation of cultured cells with TGFbeta induced the expression of pSmad2/3, S100A4 and alpha-smooth muscle actin; these cells became highly motile. Although normal bile ducts expressed ALK5 (TGFbeta RI), low levels of TGFbeta mRNA and nuclear pSmad2/3, they did not express S100A4, vimentin or MMP-2. However, TGFbeta mRNA and nuclear pSmad2/3 were strongly expressed in damaged ducts, which also expressed S100A4, vimentin and MMP-2. Fibroblast-like cells which expressed S100A4 were present around many damaged bile ducts. Cells in the 'ductular reaction' expressed both epithelial and mesenchymal markers together with high levels of TGFbeta mRNA and pSmad2/3. In conclusion, the cells forming small- and medium-sized bile ducts and the ductular reaction undergo EMT during chronic liver diseases, resulting in the formation of invasive fibroblasts; this process may be driven by a response to local TGFbeta, possibly presented by infiltrating T cells.
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PMID:Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease. 1805 63

Whether T-cell antigen receptors (TCR) on donor T cells require direct interactions with major histocompatibility complex class I or class II (MHCI/MHCII) molecules on target cells to mediate graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) is a fundamental question in allogeneic stem-cell transplantation (alloSCT). In MHC-mismatched mouse models, these contacts were not required for GVHD. However, this conclusion may not apply to MHC-matched, multiple minor histocompatibility antigen-mismatched alloSCT, the most common type performed clinically. To address this, we used wild-type (wt)-->MHCI-/- or wt-->MHCII-/- bone marrow chimeras as recipients in GVHD experiments. For GVL experiments, we used MHCI-/- or MHCII-/- chronic-phase CML cells created by expressing the BCR-ABL cDNA in bone marrow from MHCI-/- or MHCII-/- mice. TCR/MHCI contact was obligatory for both CD8-mediated GVHD and GVL. In contrast, CD4 cells induced GVHD in wt-->MHCII-/- chimeras, whereas MHCII-/- mCP-CML was GVL-resistant. Donor CD4 cells infiltrated affected skin and bowel in wt-->MHCII-/- recipients, indicating that they mediated GVHD by acting locally. Thus, CD4 cells use distinct effector mechanisms in GVHD and GVL: direct cytolytic action is required for GVL but not for GVHD. If these noncytolytic pathways can be inhibited, then GVHD might be ameliorated while preserving GVL.
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PMID:CD8+ but not CD4+ T cells require cognate interactions with target tissues to mediate GVHD across only minor H antigens, whereas both CD4+ and CD8+ T cells require direct leukemic contact to mediate GVL. 1822 70

Engagement of the TCR can induce different functional outcomes such as activation, proliferation, survival, or apoptosis. How the TCR-mediated signaling cascades generating these distinct cellular responses are organized on the molecular level is so far not completely understood. To obtain insight into this question, we analyzed TCR/CD8-mediated signaling events in mature OT-I TCR transgenic T cells under conditions of stimulation that lead to either proliferation or apoptosis. These experiments revealed major differences in the phosphorylation dynamics of LAT, ZAP70, protein kinase B, phospholipase C-gamma1, protein kinase D1, and ERK1/2. Moreover, input signals leading to apoptosis induced a strong, but transient activation of ERK1/2 mainly at sites of TCR-engagement. In contrast, stimuli promoting survival/proliferation generated a low and sustained activation of ERK1/2, which colocalizes with Ras in recycling endosomal vesicles. The transient activation of ERK1/2 under pro-apoptotic conditions of stimulation is at least partially due to the rapid polyubiquitination and subsequent degradation of ZAP70, whereas the sustained activation of ERK1/2 under survival promoting conditions is paralleled by the induction/phosphorylation of anti-apoptotic molecules such as protein kinase B and Bcl-x(L). Collectively, our data provide signaling signatures that are associated with proliferation or apoptosis of T cells.
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PMID:Dynamics of proximal signaling events after TCR/CD8-mediated induction of proliferation or apoptosis in mature CD8+ T cells. 1845 90


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