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PubMed1976

Some methodological studies on effector cells in the lymphocyte-dependent cytotoxic antibody assay.

A method of direct freezing was found to be reliable for storage of the effectors for the LDA assay, though there is a considerable loss of cells. In order to get immunologically active K cells after thawing, an important step is to leave the cells to recuperate overnight in an appropriate medium before use. A short-term storage of fresh effectors is also possible. The use of a pool of effector cells from a minimum of 3 random blood donors obviates the selection of HL-A types furthermore permits a saving of the amount of serum used. Enrichment of a B cell population by removing the cells capable of forming spontaneous rosettes with SRBC was not found to enhance cytotoxicity. Pretreatment of cells with pronase, trypsin and neuraminidase did not significantly enhance their effector activity, while papain treated cells showed a systematically increased specific lysis.

B-Lymphocytes↗

PubMed1991

Simplified quantitation of cytotoxicity by integration of specific lysis against effector cell concentration at a constant target cell concentration and measuring the area under the curve.

Experience with the lytic unit (LU) as a measure of cytolytic efficiency has indicated that its accuracy is limited, even if expressed in a logarithmic format. A new method of quantifying cytotoxicity from effector dilution assays is proposed: the area under the curve (AUC) of the Ig (E/T) ratio vs. percentage cytotoxicity plot, gives an overall measure of lytic efficiency. The AUC derived from the Briggs-Haldane kinetic model is dependent on both the kinetic parameters that determine the efficiency of effector cells (the Michaelis constant KM and the catalytic constant kcat). AUC provides an index of inhibition or stimulation of lysis, independent of whether the modulation is kinetically competitive, uncompetitive or the same AUC value. In practice the method may be applied to interpret simple cytotoxicity assay data, where effector cells are being used in standardised screening for modifiers of the cytolytic response. Illustrative data of LAK cytotoxicity influenced by dose of the LAK response modifiers IL-2, TGF beta, TDSF and 5-FU, show different relationships between lytic units, KM and AUC. These data also show a wide range in the Hill coefficient and would be consistent with a cooperative effect dependent on the effector cell efficacy. This confirms that using LU as a simple measure of cytolytic efficiency could be erroneous and suggest that cytolytic response modifiers can produce a variety of kinetic changes. The AUC method, however, provides a comparative measure of efficiency in these situations, independent of mechanism.

Cytotoxicity Tests, Immunologic↗

PubMed1990

The bone marrow as an effector T cell organ in aging.

The idea that the bone marrow (BM) might function as a T cell effector organ and might constitute a compensating system to the decreased T cell compartment in aging was examined by carrying out an analysis of T cell functions in this tissue. The Thy1+ cells, which were found to increase in their proportions with age in the BM, were sorted out from the BM of young and old mice by flow cytometry and their proliferative response to Concanavalin A (conA) stimulation was measured. The sorted Thy1+ cells responded to conA at levels comparable to those of splenocytes, with the old BM showing a significantly lower response than the young. To determine whether cells of the intact BM behave in a similar pattern to the sorted cells, we measured the responses induced by conA in unseparated BM cells of both age groups. The results showed that the patterns of proliferative response in the intact BM cells were different than those observed in splenocytes and in the Thy1+ sorted cells. Hence, cells of the old BM manifested initially higher levels of proliferation preceding that of the young BM, yet the response was apparent for a shorter duration. When we measured the conA induced proliferation of the intact BM cells in the presence of colchicine, the number of BM cells entering the first mitotic cycle was higher in the old. Thus, it seems that there are more effector T cells in the old BM, yet their response to stimulation is of shorter duration. This conclusion was also supported by the assessment of cytotoxic T lymphocytes precursor (CTLp) frequency and of CTL function of the BM. CTLp was higher in the old BM following 3 days of incubation and lower following 7 and 9 days of incubation. The old BM cells showed a reduced CTL response at the proliferative phase when stimulated for 4-7 days, yet their effector cell reactivity was either equal or more efficient than the young. To determine whether some of the differences between the two age groups were due to regulatory effects of the BM microenvironment, BM cells from young and old donors were admixed with young mouse splenocytes and stimulated with conA. The conA induced response was enhanced up to tenfold under these conditions yet to the same extent in both age groups. Thus, it appears that the BM has the capacity to function as a T cell effector organ.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗

PubMed1987

Immune and nonimmune effector functions of IgG3 mouse monoclonal antibody R24 detecting the disialoganglioside GD3 on the surface of melanoma cells.

R24, an IgG3 mouse monoclonal antibody reactive with the disialoganglioside GD3, was found to be a potent mediator of human complement cytotoxicity and human effector cell cytotoxicity. Cytotoxicity correlated with the degree of antibody binding (GD3 cell surface expression) for each of the melanoma cell lines and melanocyte cell cultures tested. Melanoma cell lines binding low amounts of R24 (low GD3 cell surface expressors) were not lysed in R24-directed immune reactions, suggesting that a threshold number of R24 molecules bound per cell is necessary to initiate these cytotoxic mechanisms. Since both complement- and cell-mediated reactions lysed the same subpopulations of cells in each cell line, both mechanisms appeared to depend on similar threshold quantities of bound R24 molecules. However, due to the heterogeneity of R24 binding in each cell line, the numerical value for this threshold could not be determined. Only in cell lines binding greater than 10(7) R24 molecules per cell were greater than 90% of the cells lysed. Normal melanocytes in culture were not lysed by R24-directed immune mechanisms, due to their low GD3 expression, indicating that monoclonal antibodies such as R24 may show tumor specificity with regard to effector functions even though normal cells express the relevant antigen. In contrast to the potent in vitro activity of R24, treatment of nu/nu mice bearing human melanoma grafts resulted in tumor inhibition only when started within 3 days of tumor cell inoculation. No effect was seen on established tumors. Thus, this in vivo mouse model failed to predict the clinical and pathological findings observed in treatment trials of R24 in human melanoma patients--urticaria involving skin metastases, cellular infiltration of tumor tissue, and tumor regression. In addition to activating immunologic effector functions, R24 had direct effects on melanoma cells, blocking their ability to attach to surfaces and causing tumor cell aggregation. These effects were again related to the number of R24 molecules bound to the cell surface; no aggregation was seen with cell lines binding less than 4 X 10(5) molecules per cell. Both immune and nonimmune effector functions may be involved in the tumor inhibitory activity of R24 in humans.

Animals↗

PubMed1982

Effects of prostaglandins on the development of cell-mediated immunity in culture and on the cytolytic activity of in vivo-generated effector cells.

This study was undertaken in an attempt to better understand the rôle of prostaglandins in the development of the primary cell-mediated immunity (CMI) response in culture. Primary sensitization cultures with C57Bl/6 mouse spleen cells as responder cells (R) and X-irradiated P815 mastocytoma cells as allogeneic stimulator cells (S) were established in the presence and absence of test agents. The ability of effector cells to lyse P815 target cells was measured by 51Cr-release assay on day 4. 3H-Thymidine uptake into the cultured cells was also analyzed on the same day. Prostaglandins of the E series were shown to exert selective effects on the CMI response depending on dose, schedule of administration, and culture conditions. PGE1 or PGE2 enhanced the CMI response at 30 pM but inhibited it by 50% at 30 nM. At an optimal R/S ratio, 30 nM PGE1, or PGE2 always inhibited 3H-thymidine uptake more than cytotoxicity while at suboptimal ratios it inhibited both equally. PGE1 did not affect the kinetics of development of the CMI responses. PGE1 was inhibitory when added 20 h before, at the same time as or as late as 24 h after antigen. The inhibitory effect was prevented by removal of PGE1 within 24 h of addition. Pretreatment of spleen cells with PGE1 for 20 h did not affect their subsequent response to sensitization. It seems that PGE1 must be present during the early phase of lymphocyte activation and that it has a relatively long half-life in spleen cell cultures. The development of secondary CMI in culture was less sensitive to inhibition by PGE than that of the primary CMI. PGD2 and PGA2 also inhibited the induction of the primary CMI while PGF2 alpha enhanced it. On the other hand, PGI2 and TXB2 had no effect. The effect of prostaglandins on the lytic activity of the in vivo-generated effector cells was also examined. The addition of PGE2, PGI2, PGD2 or PGA2 to the 51Cr-release assay resulted in significant depression of the cell-mediated lympholysis; whereas, addition of 6-keto-PGF1 alpha, TXB2, and PGF2 alpha caused little effect. PGE2, PGA2 or PGD2 inhibited the rate of lytic activity. In order to exert this effect, these compounds must be present during the 51Cr-release assay and pretreatment of the effector cells had little effect on their cytotoxicity. These results indicate that prostaglandins have immunomodulating activity affecting the early phase of the development of the CMI response in culture; they also have the ability to inhibit the cytolytic effect of effector cells generated in vivo.

Alprostadil↗

PubMed1981

Cytotoxic effector cells against HLA antigens in strong linkage disequilibrium: identification of a strong, new CML determinant.

Three sets of cytotoxic effector cells were generated against the A1, B8, DR3 haplotype using haploidentical individuals in three different families. The three sets of effector cells generated against this haplotype showed excellent reproducibility testing, strong cytotoxicity against their specific targets, low autologous kill, and segregation with the sensitizing haplotype within the family. When tested against a panel of cells bearing all combinations of the A1, B8, DR3 antigens, a hierarchy of contribution of the individual HLA antigens as CML target determinants was seen. A new strong target cell determinant was identified by cytotoxicity with one of the effector cells not explicable in terms of the A1, B8, DR3 antigens or known HLA cross-reactivity. A family study demonstrated that this determinant clearly segregates with HLA. The success of this approach in defining new CML determinants may result from the generation of effector cells across a single haplotype in strong linkage disequilibrium or from the presentation of CML determinants in the context of self.

Analysis of Variance↗

PubMed1988

Cell-mediated cytotoxicity and the reorientation of effector cell granules towards the target cell are inhibited by the protonophore carbonylcyanide m-chlorophenylhydrazone.

Cell-mediated cytotoxicity involves a localized secretory process in which lytic agents stored in specialized granules of the effector cells are released upon contact with the appropriate target cell membrane and cause membrane damage. The protonophore carbonylcyanide m-chlorophenylhydrazone (CCCP) inhibits cytotoxicity of natural killer cells, cytotoxic T-lymphocytes and lymphokine-activated killer cells. This inhibition is due to an effect of CCCP on the cytolytic cells, rather than on their targets, and is reversible. Treatment with CCCP does not inhibit the formation of effector-target conjugates, but seems to affect the programming of the effector cells for lysis. CCCP only inhibits lysis if added during a certain period of the lytic cycle: it has an effect only if added before, or within 5 minutes of the initiation of killing by a pulse of Ca++. Effector cells treated with CCCP retain their characteristic beta-glucuronidase-positive granules, but in the presence of the drug, these are no longer oriented to face the contact area with the target cell membrane.

Carbonyl Cyanide m-Chlorophenyl Hydrazone↗

PubMed1994

A mutation in the effector region of Ras2 can be partially suppressed by alteration of a 'nonessential' region of Ras.

Phenotypically normal revertants of budding yeast cells that contain the hyperactive RAS2Val19 allele often result from second-site mutations within the RAS2 locus itself. Several such intragenic revertants harboring a suppressed RAS2Val19 allele as their only RAS gene were analyzed. All such suppressors resulted from single amino acid substitutions that affected either: (i) the effector region of Ras2, (ii) the C-terminal CAAX box of Ras2, or (iii) residues known to be critical for GTP binding in Ras proteins. While these suppressor mutations completely suppressed the hyperactive phenotype induced by the Val19 substitution, they did not block the ability of Ras2 to promote growth at normal temperatures. These results suggest that in yeast, attenuation of Ras proteins can effectively block hyperactive phenotypes without completely blocking the growth-promoting function. A spontaneous intragenic mutation that restored function to an effector mutant was mapped to a 'nonessential' region of Ras proteins. Based on this genetic interaction with the effector region and the report that deletions of this region affect Ras/GAP interaction, we suggest that this region may have a functional role in Ras activation of target effectors.

Base Sequence↗

PubMed1990

Difference between antigen-binding receptor repertoires in effector cytotoxic T lymphocytes and their secondary precursors (memory cells) specific to H-2Kb.

The fine specificity of antigen-binding receptors was compared in pCTL-2 and secondary effector CTL (cytotoxic T lymphocytes) induced in vivo with the H-2Kb alloantigen in recombinant inbred mice. The lymphocyte preparations were enriched by elution from macrophage monolayers of various origins, including the donor (B6 strain), the H-2Kb mutant bm1, the H-2Kk allele B10.A(4R) and the recipient strain B10.D2(R101) as a control. Anti-Kb pCTL-2 eluted from third-party bm1 or B10.A(4R) monolayers gave rise to CTL progeny that lysed, equally well, both donor TC and those third-party TC from whose monolayer the pCTL-2 had been eluted, but which were unable to lyse irrelevant third-party TC. The lytic activities of secondary CTL whose precursors had been eluted from bm1 or B10.A(4R) monolayers were 6 and 12 times lower, respectively, than pCTL-2 eluted from the donor monolayer. Opposite results were shown for receptors of enriched secondary anti-Kb effector CTL. Irrespective of their elution source, whether donor, mutant or allele variant, the eluted effector CTL were able to lyse the donor TC to a similar degree and much more than the given third-party TC; moreover, they retained cross-reactivity in all cases. It is suggested that CTL receptors are homogeneous in specificity for a whole composite immunodominant epitope and differ from each other only in the affinity/lability of the combining site. In contrast, pCTL-2 can be separated into fractions: receptors of each fraction are strictly specific (with high affinity) to a particular portion of the same composite CTL epitope. It seems likely that the pCTL-2 receptor antigen-binding site is modified during pCTL-2 in vivo differentiation into effector CTL.

Animals↗

PubMed2005

Two Pseudomonas syringae type III effectors inhibit RIN4-regulated basal defense in Arabidopsis.

Plant cells have two defense systems that detect bacterial pathogens. One is a basal defense system that recognizes complex pathogen-associated molecular patterns (PAMPs). A second system uses disease-resistance (R) proteins to recognize type lll effector proteins that are delivered into the plant cell by the pathogen's type III secretion system. Here we show that these two pathways are linked. We find that two Pseudomonas syringae type III effectors, AvrRpt2 and AvrRpm1, inhibit PAMP-induced signaling and thus compromise the host's basal defense system. RIN4 is an Arabidopsis protein targeted by AvrRpt2 and AvrRpm1 for degradation and phosphorylation, respectively. We find that RIN4 is itself a regulator of PAMP signaling. The R proteins, RPS2 and RPM1, sense type III effector-induced perturbations of RIN4. Thus, R proteins guard the plant against type III effectors that inhibit PAMP signaling and provide a mechanistic link between the two plant defense systems.

Arabidopsis↗

PubMed2005

Programming effectors and coordination in bimanual in-phase mirror finger movements.

We investigated cerebral activation during programming of in-phase symmetric finger movements in a precued response task. Partial precues provided advance information about either mirror effectors or in-phase coordination of bimanual movements, while full precue specified both response parameters and neutral precue no movement information. Effects of precueing were assessed on reaction time (RT), contingent negative variation (CNV), and alpha and beta event-related desynchronization (ERD). Information on coordination mode induced less efficient preparation than information on effectors, as revealed by longer RT, but paradoxically the CNV was found of larger amplitude for in-phase than for mirror precue. Full and in-phase precues were associated to largest cerebral activation, as reflected by CNV amplitude as well as beta ERD. It is suggested that with in-phase precueing, abstract programming of coordination and concrete preparation of possible effectors overlap, engaging more cerebral resources than when symmetric effectors are pre-specified. Alpha ERD underwent regional modulations dependent on the type of preparation, pointing out the role of the right parietal region in visuomotor transformation with full movement programming, and the preferential implication of the dominant hemisphere and medial brain regions in synchronization of both hand movements. Beta ERD topographical distribution suggested an increased implication of bilateral and medial motor regions in anticipation to the response signal with incomplete movement preparation.

Adult↗

PubMed2005

Type-III effectors: sophisticated bacterial virulence factors.

Bacterial pathogens cause a wide spectrum of diseases in human and other animals. Some virulence factors, which are referred to as effectors, are directly translocated into the host cell via an injection apparatus, i.e., the type-III secretion system. Most effectors mimic host molecules, and translocated effectors are thereby able to perturb or modulate host cell signaling, cytoskeletal rearrangement, vesicular traffic, and autophagy, thus eliciting disease. Effectors are roughly classified among exotoxins, but in most cases, their functions are exerted focally when they are translocated into the host cell.

Animals↗

PubMed2004

EspFU is a translocated EHEC effector that interacts with Tir and N-WASP and promotes Nck-independent actin assembly.

Several microbial pathogens including enteropathogenic E. coli (EPEC) exploit mammalian tyrosine-kinase signaling cascades to recruit Nck adaptor proteins and activate N-WASP-Arp2/3-mediated actin assembly. To promote localized actin "pedestal formation," EPEC translocates the bacterial effector protein Tir into the plasma membrane, where it is tyrosine-phosphorylated and binds Nck. Enterohemorrhagic E. coli (EHEC) also generates Tir-dependent pedestals, but in the absence of phosphotyrosines and Nck recruitment. To identify additional EHEC effectors that stimulate phosphotyrosine-independent actin assembly, we systematically generated EHEC mutants containing specific deletions in putative pathogenicity-islands. Among 0.33 Mb of deleted sequences, only one ORF was critical for pedestal formation. It lies within prophage-U, and encodes a protein similar to the known effector EspF. This proline-rich protein, EspFU, is the only EHEC effector of actin assembly absent from EPEC. Whereas EHEC Tir cannot efficiently recruit N-WASP or trigger actin polymerization, EspFU associates with Tir, binds N-WASP, and potently stimulates Nck-independent actin assembly.

Actins↗

PubMed2005

AvrPtoB: a bacterial type III effector that both elicits and suppresses programmed cell death associated with plant immunity.

Pseudomonas syringae pv. tomato DC3000 is a model pathogen for studying the molecular basis of plant immunity and disease susceptibility in tomato and Arabidopsis. DC3000 uses a type III secretion system to inject effector proteins into the plant cell. Type III effectors are thought to promote bacterial virulence by suppressing plant defenses and enhancing access to nutrients trapped in the plant cell. The AvrPtoB type III effector elicits immunity-associated programmed cell death (PCD) when expressed in tomato plants carrying the Pto resistance protein. However, in the absence of Pto, AvrPtoB functions to suppress PCD and immunity in tomato. Here, we review current research examining the molecular basis of AvrPtoB-mediated elicitation and suppression of plant PCD. In addition, the "trump model" is proposed to explain how resistance proteins successfully elicit immunity-associated PCD in response to effectors that suppress PCD.

Apoptosis↗

PubMed2004

Is the learning of goal-directed displacement effector-independent?

The present experiment was designed to investigate whether the learning of goal-directed locomotion is effector independent. To answer this question a bilateral transfer of learning paradigm was used. We wanted to find out whether learning can be transferred from a trained effector system to an untrained one. Sixteen participants were asked to proceed through virtual hallways, while walking on a treadmill or handling of a joystick, in order to cross a pair of oscillating doors. Participants received 1050 training trials on the specific effector system before being transferred to the untrained one. Results indicated a clear transfer from handling to walking and only a moderate transfer from walking to handling. This asymmetrical transfer provides partial support in favor of the effector independent hypothesis. Both the theoretical implications of this work and the possible mediating effect of calibration are discussed.

Adult↗

PubMed2006

Analysis of the interaction between IFN-gamma and IFN-gammaR in the effector phase of experimental murine allergic conjunctivitis.

IFN-gamma acts to promote the severity of experimental allergic conjunctivitis (EC) during the effector phase. To identify the cell source and cell target of this cytokine in the effector phase of EC, we established mice lacking both IFN-gamma and the IFN-gamma receptor (Dbl-KO). Reciprocal adoptive transfer experiments involving wild-type, Dbl-KO, IFN-gamma-lacking and IFN-gammaR-lacking mice were performed. EC was then induced by RW challenge in eye drops. Analysis of the resulting eosinophil infiltration in the six donor/recipient combinations revealed that IFN-gamma produced by both donor and recipient cells plays an important role in the EC effector phase, and that the targets for this cytokine are also both donor and recipient cells. That EC was attenuated when any of the IFN-gamma-IFN-gammaR interactions were disturbed confirms that IFN-gamma promotes the severity of EC during the effector phase. These observations indicate that Dbl-KO mice will be useful for investigating the role(s) IFN-gamma play in inflammatory diseases.

Adoptive Transfer↗

PubMed2006

Th17: an effector CD4 T cell lineage with regulatory T cell ties.

The naive CD4 T cell is a multipotential precursor with defined antigen recognition specificity but substantial plasticity for development down distinct effector or regulatory lineages, contingent upon signals from cells of the innate immune system. The range of identified effector CD4 T cell lineages has recently expanded with description of an IL-17-producing subset, called Th17, which develops via cytokine signals distinct from, and antagonized by, products of the Th1 and Th2 lineages. Remarkably, Th17 development depends on the pleiotropic cytokine TGF-beta, which is also linked to regulatory T cell development and function, providing a unique mechanism for matching CD4 T cell effector and regulatory lineage specification. Here, we review Th17 lineage development, emphasizing similarities and differences with established effector and regulatory T cell developmental programs that have important implications for immune regulation, immune pathogenesis, and host defense.

Animals↗

PubMed2004

Crystal structure of type IIE restriction endonuclease EcoRII reveals an autoinhibition mechanism by a novel effector-binding fold.

EcoRII is a type IIE restriction endonuclease that interacts with two copies of the DNA recognition sequence 5'CCWGG, one being the actual target of cleavage, the other serving as the allosteric effector. The mode of enzyme activation by effector binding is unknown. To investigate the molecular basis of activation and cleavage mechanisms by EcoRII, the crystal structure of EcoRII mutant R88A has been solved at 2.1A resolution. The EcoRII monomer has two domains linked through a hinge loop. The N-terminal effector-binding domain has a novel DNA recognition fold with a prominent cleft. The C-terminal catalytic domain has a restriction endonuclease-like fold. Structure-based sequence alignment identified the putative catalytic site of EcoRII that is spatially blocked by the N-terminal domain. The structure together with the earlier characterized EcoRII enzyme activity enhancement in the absence of its N-terminal domain reveal an autoinhibition/activation mechanism of enzyme activity mediated by a novel effector-binding fold. This is the first case of autoinhibition, a mechanism described for many transcription factors and signal transducing proteins, of a restriction endonuclease.

Allosteric Regulation↗