Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD69 is a phosphorylated disulfide-linked homodimer that appears on the surface of human T, B cells and thymocytes in the early steps of activation; its molecular mass is 28 to 34 kDa under reducing conditions. This molecule is able to mediate positive signals to the lymphocytes as the anti-CD69 mAb (MLR3, AIM, Leu 23) in synergism with phorbol esters induce IL-2 production and proliferation of lymphocytes. Here we show that this molecule is associated to a GTP binding protein that is a substrate for Bordetella pertussis toxin. The relevance of CD69 in the activation process is also suggested by the broad range of signals able to modulate CD69 on T cells. In fact, not only the mitogens or the CD3-promoted activation, but also the alternative pathways mediated by CD2 or CD28 are accompanied by CD69 expression; moreover a very rapid and transient appearance of CD69 on the cell surface is observed also in response to a stimulus not specifically involved in T cell activation such as heat shock. Finally we demonstrate that CD69 is present in the cytoplasm of nonactivated T cells; accordingly its surface expression at the onset of activation is independent on a new RNA or protein synthesis.
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PMID:CD69 in resting and activated T lymphocytes. Its association with a GTP binding protein and biochemical requirements for its expression. 171 Feb 39

Apoptosis of natural killer (NK) cells can be induced by non-specific physical damage (UV irradiation, heat shock) or by simultaneous ligation of the CD16 and the interleukin-2 receptor (IL-2R) molecules, but not with either anti-CD16 or IL-2 alone. Whereas blockade of GTP-binding protein (G protein)-mediated signal transduction using ADP-ribosylating bacterial toxins or the GTPase-resistant GTP analog guanosine 5'-0-(3-thiotriphosphate (GTP gamma S) does not affect non-specific induction of NK cell apoptosis, such interventions do inhibit induction of apoptosis by anti-CD16/IL-2. The G proteins involved in the regulation of activation-induced NK apoptosis are sensitive to pertussis toxin (PTX) and to the non-specific GTP analog GTP gamma S but not to cholera toxin, Pseudomonas exotoxin A or diphtheria toxin. A pertussis toxin mutant that lacks ADP-ribosylating activity, but conserves the membrane translocating and T cell-mitogenic effects of the native molecule, fails to inhibit NK apoptosis. To exert their apoptosis-inhibitory effect, PTX and GTP gamma S must be employed before cells are activated. Later addition has no effect, suggesting the implication of G proteins in the transmission of apoptosis-inducing signals, but not in the effector stage of apoptosis. Pre-incubation with PTX or GTP gamma S does not affect the activation of NK cells by CD16 cross-linking, IL-2 stimulation- or both, as assessed by the induction of CD69 expression, protein tyrosine phosphorylation and calcium mobilization. Moreover, neither PTX nor GTP gamma S compromise the effector function of NK cells or the susceptibility of target cells to NK-mediated lysis. These data suggest apoptosis as a novel mechanism by which NK responses may be controlled in vivo, as well as an experimental and therapeutical strategy to counteract endogenous down-regulation of NK responses.
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PMID:Pertussis toxin-sensitive GTP-binding proteins regulate activation-induced apoptotic cell death of human natural killer cells. 748 48

Activation of human thymocytes and pre-B cells via the CD3/T cell receptor (TCR) complex or the IgM/B cell receptor complex, respectively, results in apoptotic cell death. Similarly, cross-linking of the activation marker CD69, which belongs to the natural killer complex, causes apoptosis of lipopolysaccharide-preactivated monocytes. Here we show that pertussis toxin (PTX) inhibits the activation-induced apoptosis of these three cell types, though it fails to prevent the programmed cell death that follows exposure of cells to the synthetic glucocorticoid dexamethasone (thymocytes, pre-B cells) or to interleukin 4 (monocytes). The capacity of pertussis toxin to suppress activation-induced death is not due to quenching of the activation signal, because thymocytes exposed to PTX are still capable of mobilizing Ca2+ after TCR-alpha/beta cross-linking and proliferate in response to costimulation with PTX and CD3/TCR ligation. The apoptosis-inhibitory effect of PTX depends on the presence of an intact adenosine diphosphate (ADP)-ribosylating moiety, since a mutant pertussis toxin molecule that lacks enzymatic activity, but still possesses the membrane translocating activity, fails to interfere with activation-induced cell death. A toxin that induces a different spectrum of ADP ribosylation than PTX, cholera toxin, fails to inhibit apoptosis. To suppress apoptosis, the intact PTX holotoxin must be added to cells before the lethal activation step; its addition 30 min after initial activation remains without effect on apoptosis. These data unravel a PTX sensitive signal transduction event that intervenes during an early step of activation-induced cell death of immune cells.
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PMID:Pertussis toxin inhibits activation-induced cell death of human thymocytes, pre-B leukemia cells and monocytes. 806 31

Simultaneous stimulation of human monocytes/macrophages or THP1 cells with LPS and an antibody specific for the activation marker CD69 induces apoptosis. Here we demonstrate the involvement of multiple independent signals that are necessary for apoptosis induction. Thus, inhibitors of phospholipase A2 and lipoxygenase prevent apoptosis induction. Similarly, the ADP-ribosylating G-protein-reactive pertussis toxin (PTX) but not a mutant toxin lacking the ADP-ribosylating moiety (mPTX) prevents apoptosis induction. Furthermore, inhibition of NO generation abrogates completely the induction of apoptosis by LPS/CD69 ligation. These three pathways can be dissociated from each other in the sense that interventions on the arachidonic acid metabolism or G proteins do not inhibit the generation of NO and that exogenous NO cannot reverse the inhibition of cell death by inhibitors of phospholipase A2 or PTX. In addition, both PTX and mPTX affect arachidonic acid mobilization only partially, indicating that the apoptosis-inhibitory effect of PTX (which is not shared by mPTX) cannot be explained by its effect on phospholipase A2 activation. Both LPS and anti-CD69 are sufficient on their own to activate cells, as determined by TNF production, NO generation, or arachidonic acid metabolism, but neither LPS nor anti-CD69 can induce apoptosis on their own. Thus, apoptosis induction in this system involves at least three independent signal transduction systems--(i) arachidonic acid metabolism, (ii) NO, and (iii) PTX-sensitive events--each of which is necessary but insufficient to induce monocyte/macrophage apoptosis. These findings underline the complex control of activation-induced apoptosis in cells of the myelomonocytic lineage.
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PMID:CD69-induced monocyte apoptosis involves multiple nonredundant signaling pathways. 896 80

We investigated a role of chemokines in thymocyte trafficking. Genes encoding stromal cell-derived factor-1 and its receptor CXCR4 were detected in the cortex by in situ hybridization. Early immigrant cells did not express CXCR4, whereas their descendant CD44+CD25+CD4-CD8- cells did. CXCR4 expression was down-modulated when CD4+CD8+ double-positive cells became CD4+CD8- or CD4-CD8+ single-positive (SP) cells. Positively selected CD69+CD3intermediate cells gained CCR4, of which ligand, thymus activation-regulated chemokine, was expressed in the medulla. At the next developmental stage, CD69-CD3high cells lost CCR4 but gained CCR7. These results suggest that thymocytes use different chemokines along with their development. Blockade of chemokine receptor-mediated signaling by pertussis toxin perturbed the normal distribution of SP cells and resulted in the accumulation of SP cells in the cortex. Thus, a pertussis toxin-sensitive event controls the trafficking of SP cells across the corticomedullary junction.
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PMID:Pertussis toxin-sensitive signal controls the trafficking of thymocytes across the corticomedullary junction in the thymus. 1022 36

We investigated whether pertussis toxin (PT)-sensitive heterotrimeric Gi proteins (Gi1, Gi2, Gi3) are involved in the regulation of TCR-induced activation of human T cells. First, Gi proteins were inactivated by PT: pretreatment with PT of purified blood T lymphocytes before CD3 cross-linking inhibited cell proliferation (-71.1 +/- 22.0%, P < 0.001), production of interleukin-2 (IL-2; -47.3 +/- 12.6%, P = 0.008), and expression of CD25 (-24.6 +/- 11.7%, P < 0.001) and CD69 (-25.7 +/- 9.0%, P < 0.001). Then, to identify which of the three Gi was involved, Gi1, Gi2, and Gi3 proteins were specifically inactivated by stably transfecting dominant-negative mutated forms of their alpha subunit in Jurkat cells. After activation, IL-2 production and CD69 expression were inhibited only in cells expressing inactive Gi2. We then studied the effects of interleukin-8 (IL-8), a CXC-chemokine with receptors coupled to Gi2 and produced in an autocrine fashion by activated T cells. Although its effects varied among donors, exogenous IL-8 stimulated proliferation and CD25 expression (up to, respectively, 200 and 77%) of PB T lymphocytes in response to CD3 activation, in a PT-sensitive manner. IL-8 also stimulated IL-2 production (by up to 42%) and CD69 expression, although weakly (+27%). Anti-human IL-8 antibody inhibited proliferation (-43%) and CD25 up-regulation (-45%) of activated T lymphocytes. In summary, several major responses of human T lymphocytes to TCR-mediated activation are regulated by Gi2 proteins, which for this function can be activated by IL-8 in an autocrine manner.
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PMID:Positive regulation of human T cell activation by Gi2 proteins and interleukin-8. 1081 Oct 16

T cells that emigrate from the thymus have primarily been studied in vivo using fluorescent dye injection of the thymus. This study examined the properties of thymocytes that emigrate from cultured thymic lobes in organ culture. Under these conditions, thymic emigrants displayed the expected phenotype, that of mature thymocytes expressing high levels of T-cell receptor (TCR-alphabeta) and either CD4 or CD8, and were observed to emigrate within 24 hours of positive selection. Emigration was inhibited by cytochalasin D, pertussis toxin, or Clostridium difficile toxin B, implicating an active motility process. Most of the surface markers on alphabeta-thymic emigrants (Thy1, CD44, CD69, CD25, leukocyte functional antigen-1, intercellular adhesion molecule-1, alpha(4)-integrin, alpha(5)-integrin, CD45, and CD28) were expressed at a surface density similar to that on mature intrathymic cells and peripheral splenic T cells. Heterogeneous expression of L-selectin and heat-stable antigen (HSA) suggested that subsets emerge from the thymus with a commitment to different migration patterns. The only marker on emigrants not found on either intrathymic cells or mature spleen T cells was CTLA-4, which could dampen the response of emigrants to peripheral antigens. Antigen responsivenes measured in vitro against allogeneic dendritic cells showed a proliferative response comparable to that of splenic T cells. In vivo, however, thymic emigrants failed to induce an acute graft-versus-host reaction in allogeneic severe combined immunodeficiency recipients. This suggests that a mechanism operating in vivo, perhaps tolerance or migration pattern, attenuates the response of emigrants against antigens that did not induce their deletion in the thymus.
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PMID:Thymic emigrants isolated by a new method possess unique phenotypic and functional properties. 1122 81

Experimental autoimmune encephalomyelitis was induced in macaques. T cell clones infiltrated into the brain lesion area were compared with those in blood. Intradermal immunization of macaques with brain white matter derived from healthy macaque in combination with pertussis toxin, induced neurological symptoms in two macaques. One died on day 25 after immunization, whereas the other survived. Gross examination of the brain from the dead macaque, showed clear hemorrhagic lesions in the white matter. Hematological analysis showed that drastic T cell response was induced in macaques immunized with white matter, but not in control macaques. Flow cytometric analysis of blood cells from the affected macaques demonstrated an increase of CD4 and CD8 T cell populations expressing the CD69 early activation marker. Single strand conformation polymorphism (SSCP) analysis of T cell receptor beta chain showed T cell clones infiltrated into the brain lesion, which were different from those found in the peripheral blood of the same monkey. The present paper shows that SSCP analysis of TCR is useful in studying clonality of T cells infiltrating into the brain tissue of macaque with EAE.
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PMID:Experimental autoimmune encephalomyelitis in cynomolgus monkeys. 1461 8

Dendritic cells (DCs) possess a number of unique features that distinguish them from other APCs. One such feature is their ability to trigger Ag-independent responses in T cells. Previous studies have focused on mature DCs, but the prevalence of this phenomenon in the resting-state immature DCs has never been considered. In this study, we show that, in the absence of Ag, human immature DCs trigger multiple responses in autologous primary CD4+ T cells, namely, increased motility, small Ca2+ transients, and up-regulation of CD69. These responses are particularly marked in CD4+ memory T cells. By using several experimental approaches, we found that DC-specific ICAM-3-grabbing nonintegrin plays no role in the induction of T cell responses, whereas ICAM-1/LFA-1 interactions are required. In addition, DC-produced chemokines contribute to the Ag-independent T cell stimulatory ability of DCs, because pertussis toxin-treated T cells exhibit diminished responses to immature DCs. More particularly, CCL17 and CCL22, which are constitutively produced by immature DCs, mediate both T cell polarization and attraction. Thus, immature DCs owe part of their outstanding Ag-independent T cell stimulatory ability to chemokines and ICAM-1, but not DC-specific ICAM-3-grabbing nonintegrin.
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PMID:Immature dendritic cells (DCs) use chemokines and intercellular adhesion molecule (ICAM)-1, but not DC-specific ICAM-3-grabbing nonintegrin, to stimulate CD4+ T cells in the absence of exogenous antigen. 1521 Jul 58

We observed a remarkable reduction in the frequency and immunosuppressive activity of splenic CD4+CD25+ T cells in C57BL/6 mice with MOG33-55-induced experimental autoimmune encephalomyelitis (EAE). Our study revealed that pertussis toxin (PTx), one component of the immunogen used to induce murine EAE, was responsible for down-regulating splenic CD4+CD25+ cells. Treatment of normal BALB/c mice with PTx in vivo reduced the frequency, suppressive activity and FoxP3 expression by splenic CD4+CD25+ T cells. However, PTx treatment did not alter the expression of characteristic phenotypic markers (CD45RB, CD103, GITR and CTLA-4) and did not increase the expression of CD44 and CD69 by the residual splenic and lymph node CD4+CD25+ T cells. This property of PTx was attributable to its ADP-ribosyltransferase activity. PTx did not inhibit suppressive activity of purified CD4+CD25+ T regulatory (Treg) cells in vitro, but did so in vivo, presumably due to an indirect effect. Although the exact molecular target of PTx that reduces Treg activity remains to be defined, our data suggests that alteration of both distribution and function of splenic immunocytes should play a role. This study concludes that an underlying cause for the immunological adjuvanticity of PTx is down-regulation of Treg cell number and function.
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PMID:Pertussis toxin as an adjuvant suppresses the number and function of CD4+CD25+ T regulatory cells. 1647 42


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