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At least 649 records · Page 36Linked to original sources
PubMed1999

The activated type 1-polarized CD8(+) T cell population isolated from an effector site contains cells with flexible cytokine profiles.

The capacity of activated T cells to alter their cytokine expression profiles after migration into an effector site has not previously been defined. We addressed this issue by paired daughter analysis of a type 1-polarized CD8(+) effector T cell population freshly isolated from lung parenchyma of influenza virus-infected mice. Single T cells were activated to divide in vitro; individual daughter cells were then micromanipulated into secondary cultures with and without added IL-4 to assess their potential to express type 2 cytokine genes. The resultant subclones were analyzed for type 1 and 2 cytokine mRNAs at day 6-7. When the most activated (CD44(high)CD11a(high)) CD8(+) subpopulation from infected lung was compared with naive or resting (CD44(low)CD11a(low)) CD8(+) cells from infected lung and from normal lymph nodes (LNs), both clonogenicity and plasticity of the cytokine response were highest in the LN population and lowest in the activated lung population, correlating inversely with effector function. Multipotential cells were nevertheless detected among clonogenic CD44(high)CD11a(high) lung cells at 30-50% of the frequency in normal LNs. The data indicate that activated CD8(+) T cells can retain the ability to proliferate and express new cytokine genes in response to local stimuli after recruitment to an effector site.

Animals↗
PubMed2001

CD8(+) T cell-mediated injury in vivo progresses in the absence of effector T cells.

Tissue injury is a common sequela of acute virus infection localized to a specific organ such as the lung. Tissue injury is an immediate consequence of infection with lytic viruses. It can also result from the direct destruction of infected cells by effector CD8(+) T lymphocytes and indirectly through the action of the T cell-derived proinflammatory cytokines and recruited inflammatory cells on infected and uninfected tissue. We have examined CD8(+) T cell-mediated pulmonary injury in a transgenic model in which adoptively transferred, virus-specific cytotoxic T lymphocytes (CTLs) produce lethal, progressive pulmonary injury in recipient mice expressing the viral target transgene exclusively in the lungs. We have found that over the 4-5 day course of the development of lethal pulmonary injury, the effector CTLs, while necessary for the induction of injury, are present only transiently (24-48 h) in the lung. We provide evidence that the target of the antiviral CD8(+) T cells, the transgene expressing type II alveolar cells, are not immediately destroyed by the effector T cells. Rather, after T cell-target interaction, the type II alveolar cells are stimulated to produce the chemokine monocyte chemoattractant protein 1. These results reinforce the concept that, in vivo, the cellular targets of specific CTLs may participate directly in the development of progressive tissue injury by activating in response to interaction with the T cells and producing proinflammatory mediators without sustained in vivo activation of CD8(+) T cell effectors.

Adoptive Transfer↗
PubMed2003

PD-1 inhibits antiviral immunity at the effector phase in the liver.

Unlike naive T cells, effector T cells can be activated by either T cell receptor signal or costimulatory signal alone and therefore the absence of costimulatory molecules on tissue cells cannot explain the tolerance mechanism at the effector phase. Here we report that PD-L1, the ligand for the immunoinhibitory receptor PD-1, was expressed on vascular endothelium in peripheral tissues. Liver nonparenchymal cells including sinusoidal endothelial cells and Kupffer cells constitutively expressed PD-L1 and inhibited proliferation and cell division of activated T cells expressing PD-1. The absence of PD-1 induced proliferation of effector T cells in the adenovirus-infected liver and resulted in rapid clearance of the virus. These results indicate that PD-1 plays an important role in T cell tolerance at the effector phase and the blockade of the PD-1 pathway can augment antiviral immunity.

Animals↗
PubMed2005

Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen.

Transfer of naive antigen-specific CD4(+) T cells into lymphopenic mice that express an endogenous antigen as a systemic, secreted protein results in severe autoimmunity resembling graft-versus-host disease. T cells that respond to this endogenous antigen develop into effector cells that cause the disease. Recovery from this disease is associated with the subsequent generation of FoxP3(+)CD25(+) regulatory cells in the periphery. Both pathogenic effector cells and protective regulatory cells develop from the same antigen-specific T cell population after activation, and their generation may occur in parallel or sequentially. Interleukin (IL)-2 plays a dual role in this systemic T cell reaction. In the absence of IL-2, the acute disease is mild because of reduced T cell effector function, but a chronic and progressive disease develops late and is associated with a failure to generate FoxP3(+) regulatory T (T reg) cells in the periphery. Thus, a peripheral T cell reaction to a systemic antigen goes through a phase of effector cell-mediated pathology followed by T reg cell-mediated recovery, and both require the growth factor IL-2.

Animals↗
PubMed2006

Induction of a virus-specific effector-memory CD4+ T cell response by attenuated SIV infection.

We investigated simian immunodeficiency virus (SIV)-specific CD4+ T cell responses in rhesus macaques chronically infected with attenuated or pathogenic SIV strains. Analysis of SIVDeltanef-infected animals revealed a relatively high frequency of SIV-specific CD4+ T cells representing 4-10% of all CD4+ T lymphocytes directed against multiple SIV proteins. Gag-specific CD4+ T cells in wild-type SIV-infected animals were 5-10-fold lower in frequency and inversely correlated with the level of plasma viremia. SIV-specific CD4+ cells from SIVDeltanef animals were predominantly CD27-CD28-CD45RAlowCCR7-CCR5-, consistent with an effector-memory subset, and included a fully differentiated CD45RA+CCR7- subpopulation. In contrast, SIV-specific CD4+ T cells from SIV-infected animals were mostly CD27+CD28+CD45RA-CCR7+CCR5+, consistent with an early central memory phenotype. The CD45RA+CCR7-CD4+ subset from SIVDeltanef animals was highly enriched for effector CD4+ T cells, as indicated by the perforin expression and up-regulation of the lysosomal membrane protein CD107a after SIV Gag stimulation. SIV-specific CD4+ T cells in attenuated SIV-infected animals were increased in frequency in bronchioalveolar lavage and decreased in lymph nodes, consistent with an effector-memory T cell population. The ability of SIVDeltanef to induce a high frequency virus-specific CD4+ T cell response with direct effector function may play a key role in protective immunity produced by vaccination with attenuated SIV strains.

Animals↗
PubMed2003

Comparative analysis of type III effector translocation by Yersinia pseudotuberculosis expressing native LcrV or PcrV from Pseudomonas aeruginosa.

The homologues LcrV of Yersinia species and PcrV of Pseudomonas aeruginosa are pore-forming components. When expressed in a Yersinia lcrV background, PcrV formed smaller pores in infected erythrocyte membranes, correlating to a lowered translocation of Yersinia effectors. To understand this phenomenon, cytotoxins exoenzyme S of P. aeruginosa and YopE of Yersinia were introduced into a Yersinia background without Yop effectors but expressing LcrV or PcrV. Comparable translocation of each substrate indicated that substrate recognition by LcrV/PcrV is not a regulator of translocation. Yersinia harboring pcrV coexpressed with its native operon efficiently translocated effectors into HeLa cell monolayers and formed large LcrV-like pores in erythrocyte membranes. Thus, a PcrV complex with native P. aeruginosa translocon components is required to form fully functional pores for complete complementation of effector translocation in Yersinia.

Antigens, Bacterial↗
PubMed1981

Augmentation of human natural killer cell activity by interferon: conditions required for boosting and characteristics of the effector cells.

Human effector cells of natural killer (NK) activity have been augmented by pretreatment with a partially purified preparation of interferon (IFN-beta). Using the 4-hr 51Cr release assay to measure cytotoxicity, the boosted effector cells, as well as the spontaneous NK cells, were nonphagocytic cells with receptors for the Fc portion of IgG. Augmentation of cytolytic activity occurred: (1) in medium with either fetal calf serum and human serum; (2) in the presence of absence of monocytes; (3) in both sheep RBC rosette-forming and non-rosette-forming populations; and (4) when only the effector cells were pretreated with interferon. This last observation led to the finding that less than or equal to 5 min of contact at 37 degrees C, 22 degrees C, or 4 degrees C with interferon was necessary for augmentation of cytotoxicity. Augmentation kinetics demonstrated significant boosting of NK activity in peripheral blood leukocytes and highly NK-enriched Percoll fractions after 1 hr of contact with IFN-beta or pure IFN-alpha-Collectively, these results indicate that NK boosting with interferon: (1) occurs after a rapid temperature-independent binding to the effector cells; and (2) has a rapid effect on the cytolytic process.

Blood↗
PubMed1994

Raf-1 interferes with Ras and Rap1A effector functions in yeast.

Raf-1 is a serine/threonine kinase that acts downstream of Ras in mitogenic signal transduction pathways, but the mechanism by which Ras transmits signals to Raf-1 is not known. We have examined the interaction between Raf-1 and human H-ras in three different systems that utilize H-ras-induced phenotypes in Saccharomyces cerevisiae. In each system, the effects of H-ras depend on guanosine triphosphate and appear to be mediated through the H-ras effector binding region. H-ras effector function was blocked in each case by expression of the N-terminal regulatory domain of Raf-1. These inhibitory effects did not require the Raf-1 kinase domain. Raf-1 also blocked Rap1A effector function in S. cerevisiae. Raf-1, therefore, appears to interact with H-Ras and Rap1A in these in vivo systems with properties that suggest it is an immediate downstream effector.

Cell Cycle Proteins↗
PubMed1997

A T42A Ran mutation: differential interactions with effectors and regulators, and defect in nuclear protein import.

Ran, the small, predominantly nuclear GTPase, has been implicated in the regulation of a variety of cellular processes including cell cycle progression, nuclear-cytoplasmic trafficking of RNA and protein, nuclear structure, and DNA synthesis. It is not known whether Ran functions directly in each process or whether many of its roles may be secondary to a direct role in only one, for example, nuclear protein import. To identify biochemical links between Ran and its functional target(s), we have generated and examined the properties of a putative Ran effector mutation, T42A-Ran. T42A-Ran binds guanine nucleotides as well as wild-type Ran and responds as well as wild-type Ran to GTP or GDP exchange stimulated by the Ran-specific guanine nucleotide exchange factor, RCC1. T42A-Ran.GDP also retains the ability to bind p10/NTF2, a component of the nuclear import pathway. In contrast to wild-type Ran, T42A-Ran.GTP binds very weakly or not detectably to three proposed Ran effectors, Ran-binding protein 1 (RanBP1), Ran-binding protein 2 (RanBP2, a nucleoporin), and karyopherin beta (a component of the nuclear protein import pathway), and is not stimulated to hydrolyze bound GTP by Ran GTPase-activating protein, RanGAP1. Also in contrast to wild-type Ran, T42A-Ran does not stimulate nuclear protein import in a digitonin permeabilized cell assay and also inhibits wild-type Ran function in this system. However, the T42A mutation does not block the docking of karyophilic substrates at the nuclear pore. These properties of T42A-Ran are consistent with its classification as an effector mutant and define the exposed region of Ran containing the mutation as a probable effector loop.

Amino Acid Substitution↗
PubMed2001

CD11b expression as a marker to distinguish between recently activated effector CD8(+) T cells and memory cells.

CD8(+) T cells in different activation states have been difficult to identify phenotypically. In this study we have investigated whether Mac-1 (CD11b) expression can be used as a criterion to distinguish between recently activated effector cells and memory cells belonging to the CD8(+) T cell subset. Polyclonal virus-specific effector and memory CD8(+) T cells from lymphocytic choriomeningitis- and vesicular stomatitis virus-infected mice were visualized through staining for intracellular IFN-gamma or binding of MHC-peptide tetramers, and Mac-1 expression was evaluated. Naive T cells and most virus-specific memory CD8(+) T cells express little or no Mac-1 independent of the virus model employed. In contrast, the majority of CD8(+) T cells present during acute infection express a significant level of Mac-1 and, similarly, Mac-1 expression is found on secondary effectors generated in response to viral re-exposure. We therefore suggest that high Mac-1 expression defines a subset of circulating effector cells and that the presence of this marker on antigen-specific CD8(+) T cells signifies recent activation.

Acute Disease↗
PubMed1997

Altered effector responses of H-Y transgenic CD8+ cells.

The primary role of CD8+ T cells is to destroy virus-infected or tumor cells expressing cognate antigens in the form of peptide-MHC class I complexes. This destruction is primarily achieved by the actions of lytic mediators and/or lymphokines. In this report, we show that mature, H-Y/Db-specific CD8+ T cells from H-Y TCR transgenic mice were unable to efficiently release lytic mediators after antigenic stimulation. However, anti-TCR antibody induced granule exocytosis and target cell lysis, arguing against signaling and/or cytolytic machinery defects in CD8+ cells, and demonstrating that male antigen induced differentiation of 'naive' into effector CD8+ cells. Stimulation of H-Y-specific effector CD8+ T cells with male stimulators, although insufficient to induce lytic granule release, was sufficient for H-Y-specific IFN-gamma production. Unexpectedly, this effector-phase IFN-gamma production was dependent on B7-2 engagement. We hypothesize that altered effector functions in H-Y-specific CD8+ cells are due to the low affinity of TCR-antigen-MHC interaction and/or the elevated threshold of CD8+ T cell activation.

Animals↗
PubMed2004

Mechanisms of tolerance induced by transforming growth factor-beta-treated antigen-presenting cells: CD8 regulatory T cells inhibit the effector phase of the immune response in primed mice through a mechanism involving Fas ligand.

Transforming growth factor (TGF)-beta-treated antigen-presenting cells [(APC) adherent peritoneal exudate cells] induce a profound tolerance in primed mice that is thought to be mediated by regulatory T cells induced in the spleen. In the current study, we investigated the mechanism(s) involved in tolerance induced in primed mice by TGF-beta-treated APC. Interestingly, TGF-beta-treated APC from class II knockout mice were unable to mediate tolerance in primed mice and failed to induce not only CD4, but also CD8 regulatory T cells. However, the results of several experiments indicated that it was the CD8 regulatory T cells that were required for tolerance induced in primed mice. Using neutralizing antibody, we found that TGF-beta-treated APC-induced CD8 regulatory T cells did not suppress effector T cell function in vivo through the production of IL-4, TGF-beta or IL-10. On the other hand, our data showed that the Fas-Fas ligand (FasL) pathway was involved in this form of tolerance since TGF-beta-treated APC could not mediate tolerance in primed FasL-deficient mice and CD8 T cells from FasL-deficient mice were unable to suppress effector T cell responses. Moreover, the targets of FasL-mediated suppression were found to be the effector T cells as suggested by the data showing that Fas-deficient effector T cells were not susceptible to suppression mediated by CD8 regulatory T cells induced by TGF-beta-treated APC. In conclusion, our data indicate that TGF-beta-treated APC effect tolerance in primed mice via a Fas-FasL-mediated mechanism that requires CD8 cells.

Animals↗
PubMed2001

Cooperative binding of effectors by an allosteric ribozyme.

An allosteric ribozyme that requires two different effectors to induce catalysis was created using modular rational design. This ribozyme construct comprises five conjoined RNA modules that operate in concert as an obligate FMN- and theophylline-dependent molecular switch. When both effectors are present, this 'binary' RNA switch self-cleaves with a rate enhancement of approximately 300-fold over the rate observed in the absence of effectors. Kinetic and structural studies implicate a switching mechanism wherein FMN binding induces formation of the active ribozyme conformation. However, the binding site for FMN is rendered inactive unless theophylline first binds to its corresponding site and reorganizes the RNA structure. This example of cooperative binding between allosteric effectors reveals a level of structural and functional complexity for RNA that is similar to that observed with allosteric proteins.

Base Sequence↗
PubMed2002

A gene in the Pseudomonas syringae pv. tomato Hrp pathogenicity island conserved effector locus, hopPtoA1, contributes to efficient formation of bacterial colonies in planta and is duplicated elsewhere in the genome.

The ability of Pseudomonas syringae to grow in planta is thought to be dependent upon the Hrp (type III secretion) system and multiple effector proteins that this system injects into plant cells. ORF5 in the conserved effector locus of the P. syringae pv. tomato DC3000 Hrp pathogenicity island was shown to encode a Hrp-secreted protein and to have a similarly secreted homolog encoded in an effector-rich pathogenicity island located elsewhere in the genome. These putative effector genes were designated hopPtoA1 and hopPtoA2, respectively. DNA gel blot analysis revealed that sequences hybridizing with hopPtoA1 were widespread among P. syringae pathovars, and some strains, like DC3000, appear to have two copies of the gene. uidA transcriptional fusions revealed that expression of hopPtoA1 and hopPtoA2 can be activated by the HrpL alternative sigma factor. hopPtoA1 and hopPtoA1/hopPtoA2 double mutants were not obviously different from wild-type P. syringae pv. tomato DC3000 in their ability to produce symptoms or to increase their total population size in host tomato and Arabidopsis leaves. However, confocal laser-scanning microscopy of GFP (green fluorescent protein)-labeled bacteria in Arabidopsis leaves 2 days after inoculation revealed that the frequency of undeveloped individual colonies was higher in the hopPtoA1 mutant and even higher in the hopPtoA1/hopPtoA2 double mutant. These results suggest that hopPtoA1 and hopPtoA2 contribute redundantly to the formation of P. syringae pv. tomato DC3000 colonies in Arabidopsis leaves.

Amino Acid Sequence↗
PubMed2004

Identification of a novel Pseudomonas syringae Psy61 effector with virulence and avirulence functions by a HrpL-dependent promoter-trap assay.

The hrp pathogenicity island of Pseudomonas syringae encodes a type III secretion system (TTSS) that translocates effectors into plant cells. Most genes encoding effectors are dispersed in the P. syringae genome. Regardless of location, all are regulated coordinately by the alternative sigma factor HrpL. An HrpL-dependent promoter-trap assay was developed to screen genomic libraries of P. syringae strains for promoters whose activity in Escherichia coli is dependent on an inducible hrpL construct. Twenty-two HrpL-dependent promoter fragments were isolated from P. syringae Psy61 that included promoters for known HrpL-dependent genes. One fragment also was isolated that shared no similarity with known genes but retained a near consensus HrpL-dependent promoter. The sequence of the region revealed a 375-amino acid open reading frame encoding a 40.5-kDa product that was designated HopPsyL. HopPsyL was structurally similar to other secreted effectors and carried a putative chloroplast-targeting signal and two predicted transmembrane domains. HopPsyL':'AvrRpt2 fusions were translocated into host cells via the P. syringae pv. tomato DC3000 hrp TTSS. A hopPsyL::kan mutant of Psy61 exhibited strongly reduced virulence in Phaseolus vulgaris cv. Kentucky Wonder, but did not appear to act as a defense response suppressor. The ectopically expressed gene reduced the virulence of Pseudomonas syringae DC3000 transformants in Arabidopsis thaliana Col-0. The gene was shown to be conserved in 6 of 10 P. syringae pv. syringae strains but was not detected in 35 strains of other pathovars. HopPsyL appears to be a novel TTSS-dependent effector that functions as a host-species-specific virulence factor in Psy61.

Arabidopsis↗
PubMed1993

Effector functions of helper T cells.

We have reviewed the basic pathways of postthymic development of CD4 T cells (Th) and attempted to pinpoint the regulatory events that lead to the formation of functional effectors and/or the polarization of their patterns of cytokine secretion, which endow CD4 T cells with distinct functions. One finding of these studies is that the major role of naive cells is not to carry out regulatory functions, but rather to serve as precursors of the effector and memory populations. We have shown not only the particularly impressive capacity of effector populations generated in vivo and in vitro to secrete cytokines upon restimulation, but also the impressive helper function of both primary and memory effectors, which make Th2-like patterns of cytokines.

Animals↗
PubMed2002

Structural factors increase blood pressure through the interaction of resistance vessel geometry with neurohumoral and local factors: estimates in rabbits with renal cellophane-wrap hypertension with intact effectors and during neurohumoral blockade.

BACKGROUND: The structural changes in hypertension include narrowing of the lumen of the large resistance vessels and an increase in their wall thickness : lumen ratio. Their haemodynamic role has been controversial. OBJECTIVE: To examine resting haemodynamics and the responses to graded drug-induced changes in tone in renal cellophane-wrap (wrap) and sham-operated (sham) rabbits, when their neurohumoral effectors were intact and during high-level blockade. METHODS: Each rabbit was implanted with a flow probe for measuring cardiac output, had catheters inserted for drug infusions, and underwent mean arterial pressure (MAP) measurements. Resting values were determined and we infused graded doses of dilator and constrictor drugs: acetylcholine or adenosine; angiotensin II or methoxamine. The dilator and constrictor dose-response curves were combined into a single relationship for MAP, cardiac output, total peripheral conductance (TPC) and heart rate; total peripheral resistance (TPR) was estimated as 1/TPC. RESULTS: Throughout the range of vascular tone and with intact effector function, MAP was greater and TPC lower in wrap than in sham rabbits, and cardiac output was the same in both groups. The ratios of wrap : sham slopes of the log dose-response regression lines were 0.47 for TPC, 2.04 for TPR and 1.89 for MAP. Thus MAP and TPR responses were enhanced to the same degree in wrap rabbits. During neurohumoral block, baroreflex-mediated heart rate responses were abolished. In addition, resting vascular tone was lower than with intact effectors in both wrap and sham rabbits; however, the ratios of wrap : sham slopes for TPC and TPR were similar to those with intact effectors, whereas the ratio for the slope for MAP was slightly smaller, although still enhanced. CONCLUSION: In wrap hypertension, the enhanced MAP and TPR responses are in accord with an interaction between vascular geometry and the sum of altered neurohumoral + local activity, plus a rarefaction component.

Adenosine↗
PubMed1978

Effect of cortisone acetate on effector cells for antibody-mediated cytotoxicity in mouse and rat.

We have looked at the effect of in vivo cortisone acetate treatment on effector cells for antibody-dependent cell-mediated cytotoxicity in mice and rats, using both chicken erythrocytes and the mouse lymphoma cell line AKR.A as target cells, since the AKR.A cell line is susceptible to antibody-dependent cell-mediated cytotoxicity killing only by the lymphoid effector cell, whereas a wide variety of effector cells will lyse chicken erythrocytes in the presence of antibody. The lymphoid K cell, detectable in rat spleen and blood, was unaffected by steroid treatment sufficient to cause lymphopenia, whereas splenic anti-chicken erythrocyte cytotoxicity of whole spleen and of phagocyte-free spleen was depressed in mice and rats. The greatest suppression was seen with nonphagocytic mouse spleen, and may have been in part attributable to steroid-induced redistribution of the effector cell(s), since the cytotoxic capacity of nonphagocytic bone marrow cells was increased by 70% at a time when the activity in spleen was 25% of normal.

Animals↗