Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “effector”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,369 records · Page 76Linked to original sources
PubMed1997

Distinct roles for B7-1 and B7-2 determinants during priming of effector CD8+ Tc1 and regulatory CD4+ Th2 cells for contact hypersensitivity.

Contact hypersensitivity (CHS) is a CD8+ T cell-mediated response to hapten sensitization and challenge of the epidermis. Both the IFN-gamma-producing effector CD8+ T cells and the IL-4/IL-10-producing CD4+ T (Th2) cells that restrict the magnitude and duration of the response are primed by hapten-presenting Langerhans cells (hpLC). hpLC isolated from hapten-sensitized animals expressed high levels of B7-2 and lower levels of B7-1, suggesting the availability of each molecule to provide costimulation during CD8+ and CD4+ T cell priming for CHS. Anti-B7-2 Ab given during hapten sensitization inhibited effector CD8+ and regulatory CD4+ T cell development and the magnitude of the CHS response. Cytokine production by CD8+ and CD4+ T cells was reduced in anti-B7-2 Ab-treated animals, indicating that costimulation for T cell development was not compensated by hpLC-expressed B7-1. Anti-B7-1 Ab inhibited CHS and increased the number of Th2 cells primed during hapten sensitization without inhibiting development of the IFN-gamma-producing CD8+ T cells. Depletion of CD4+ T cells, however, abrogated the inhibitory effect of anti-B7-1 Ab on the CHS response, indicating the amplified Th2 response mediated this inhibition. These results indicate a requirement for B7-2 costimulation by effector CD8+ and regulatory CD4+ T cells during priming for CHS. The ability of anti-B7-1 Abs to amplify the regulatory CD4+ Th2 component and inhibit CHS suggests a strategy to inhibit unwanted CD8+ T cell-mediated immune responses to Ags in the skin.

Animals↗
PubMed1998

Purification of L-selectin(low) cells promotes the generation of highly potent CD4 antitumor effector T lymphocytes.

Successful adoptive immunotherapy of cancer requires the identification, isolation, and expansion of tumor-specific immune effector cells. A reliable source of tumor-immune lymphocytes is lymph nodes draining a growing tumor. After in vitro stimulation with anti-CD3 and expansion in IL-2, these cells are capable of mediating the regression of established tumors. In the absence of further Ag stimulation, we recently found that the down-regulation of the homing molecule L-selectin could serve as a surrogate marker for isolation of specific tumor-sensitized T cells. The L-selectin(low) (L-selectin-) T cells proliferated more vigorously than unfractionated or L-selectin(high) cells. In adoptive immunotherapy of established intracranial MCA 205 tumors, L-selectin- cells displayed at least 30-fold greater therapeutic efficacy than unfractionated cells. L-selectin(high) cells did not demonstrate any antitumor effects. Activated L-selectin- cells secreted a number of cytokines, including IFN-gamma, IL-2, IL-4, and IL-10, specifically when stimulated with cognate tumor cells. Further analysis revealed that CD4 T cells alone mediated tumor regression and secreted cytokines. Our results thus demonstrate that the purification of L-selectin- cells led to the generation of CD4 immune effector cells with unusually high therapeutic efficacy against chemically induced tumors. The lack of cytotoxicity and the ability to secrete cytokines suggest that these effector CD4 cells mediate antitumor effects through an indirect mechanism similar to the delayed hypersensitivity reaction.

Animals↗
PubMed1998

CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells.

Thymectomy of susceptible strains of mice on day 3 of life results in a spectrum of organ-specific autoimmunity that can be prevented by reconstitution of the thymectomized animals early in life with normal adult lymphocytes. The effectors and suppressors of autoimmunity in this model have been convincingly shown to be CD4+ T cells. It has been demonstrated recently that the regulatory CD4+ T cells that prevent disease coexpress CD25. We have further characterized the population of CD4+CD25+ immunoregulatory cells and demonstrated that they can suppress not only the induction of disease post-thymectomy, but can also efficiently suppress disease induced by cloned autoantigen-specific effector cells. Furthermore, the CD4+CD25+ T cells appear to be members of a unique lineage of regulatory T cells, as the induction of CD25 expression on a monospecific population of T cells derived from TCR transgenic SCID mice did not result in suppression of post-thymectomy autoimmunity. In addition, the TCR transgenic SCID mice were highly susceptible to autoimmune disease induced by the cloned line of autoantigen-specific effectors, while normal mice were relatively resistant. The capacity of the cloned line to transfer disease to nu/nu recipients could be inhibited by normal spleen cell populations containing CD4+CD25+ cells and by purified CD4+CD25+ cells. Although the target Ag(s) and mechanism of action of the CD4+CD25+ T cells remain to be determined, it is likely that they also play an important role in modulating other autoimmune diseases that are mediated by activation of "ignorant" self-reactive T cells present in the normal peripheral lymphocyte pool.

Animals↗
PubMed1998

Newborn mice develop balanced Th1/Th2 primary effector responses in vivo but are biased to Th2 secondary responses.

Newborn mice are impaired in their abilities to mount protective immune responses. For decades, it was generally held that the poor responses of newborns were largely due to the developmentally immature state of the T cells. In vitro studies showing that neonatal T cells were deficient in Th1 cytokine production, proliferation, and secondary responsiveness strongly supported this idea. Recently, several studies have challenged this view; animals exposed to Ag as neonates were shown to have mature Th1 responses in adulthood. However, it is not clear whether the mature immune responses were actually mounted by T cells generated after the neonatal stage. We have reexamined this issue by analyzing the capabilities of neonatal lymph node T cells to develop into Ag-specific effector cells during the actual neonatal period. Our results demonstrate that the capacity to develop a balanced Th1/Th2 primary effector response is fully mature within the first week of life. However, while neonatal and adult primary cytokine profiles were very similar, Th2 secondary responses predominated in animals first immunized as newborns. Moreover, we have observed other differences between adults and neonatal responses, including 1) the kinetics of cytokine production and responsiveness to adjuvant during the primary response, and 2) the contribution of spleen and lymph node to secondary responses. We propose that these differences reflect developmental regulation of effector cell function that has important consequences to neonatal immune function.

Animals↗
PubMed1998

Interleukin-12 promotes activation of effector cells that induce a severe destructive granulomatous form of murine experimental autoimmune thyroiditis.

Granulomatous inflammatory lesions are a major histopathological feature of a wide spectrum of human infectious and autoimmune diseases. Experimental autoimmune thyroiditis (EAT) with granulomatous histopathological features can be induced by mouse thyroglobulin (MTg)-sensitized spleen cells activated in vitro with MTg and anti-interleukin-2 receptor (anti-IL-2R), anti-IL-2, or anti-interferon-gamma (anti-IFN-gamma) monoclonal antibody (MAb). These studies suggested that IFN-gamma-producing T cells requiring IL-2 for growth may negatively regulate activation of granulomatous EAT effector cells. As IL-12 promotes activation of IFN-gamma-producing Th1 cells, the present study was undertaken to determine the role of IL-12 in activation of effector cells for granulomatous EAT. MTg-sensitized cells activated in vitro with MTg, anti-IL2R MAb, and IL-12 induced severe, destructive granulomatous thyroiditis with neutrophil inflammation, fibrin deposition, and necrosis. Many glands ultimately underwent atrophy and became fibrotic; some also showed fibrinoid necrosis and a mixed inflammatory cell infiltration of blood vessel walls indicative of a necrotizing vasculitis. Induction of severe granulomatous EAT by IL-12 required MTg in vitro and was unrelated to the IL-12-induced increase in IFN-gamma production. IL-12 markedly increased IFN-gamma production but did not induce a shift to a Th1-dominant phenotype, as other Th1 and Th2 cytokines were generally unaffected and both Th1 and Th2 cytokines were expressed in recipient thyroids. Addition of IL-12 or neutralization by anti-IL-12 at various times indicated that IL-12 exerted its primary effects in the final 24 hours of the 72-hour culture and was not required in recipient mice. Cells cultured with anti-IL-12, MTg, and anti-IL2R MAb transferred mild lymphocytic EAT but little or no granulomatous EAT. Thus, IL-12 profoundly regulates the in vitro activation of effector cells that induce histologically distinct autoimmune inflammatory lesions in the thyroid.

Animals↗
PubMed1998

Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus.

There are many examples of a single receptor coupling directly to more than one cellular signal transduction pathway. Although traditional receptor theory allows for activation of multiple cellular effectors by agonists, it predicts that the relative degree of activation of each effector pathway by an agonist (relative efficacy) must be the same. In the current experiments, we demonstrate that agonists at the human serotonin2A (5-HT2A) and 5-HT2C receptors activate differentially two signal transduction pathways independently coupled to the receptors [phospholipase C (PLC)-mediated inositol phosphate (IP) accumulation and phospholipase A2 (PLA2)-mediated arachidonic acid (AA) release]. The relative efficacies of agonists differed depending on which signal transduction pathway was measured. Moreover, relative to 5-HT, some 5-HT2C agonists (e.g., 3-trifluoromethylphenyl-piperazine) preferentially activated the PLC-IP pathway, whereas others (e.g., lysergic acid diethylamide) favored the PLA2-AA pathway. In contrast, when two dependent responses were measured (IP accumulation and calcium mobilization), agonist relative efficacies were not different. These data strongly support the hypothesis termed "agonist-directed trafficking of receptor stimulus" recently proposed by Kenakin [Trends Pharmacol Sci 16:232-238 (1995)]. Concentration-response curves to 5-HT2C agonists were fit well by a three-state model of receptor activation, suggesting that two active receptor states may be sufficient to explain pathway-dependent agonist efficacy. Rational drug design that optimizes preferential effector activity within a group of receptor-selective drugs holds the promise of increased selectivity in clinically useful agents.

Animals↗
PubMed1998

Synthesized allosteric effectors of the hemoglobin molecule: a possible mechanism for improved erythrocyte oxygen release capability in hemoglobinopathy H disease.

Patients with the nondeletion genotype of hemoglobinopathy H (HbH or beta4) disease have higher proportions of HbH and more severe tissue hypoxia than patients with the deletion genotype. Because these patients' red blood cells (RBCs) contain mainly two Hb species, HbH and HbA, the high proportion of HbA can be exploited by lowering its oxygen affinity; this would probably increase oxygen delivery to the RBCs and improve the patients' clinical phenotype. Allosteric effectors that induce a low-affinity Hb may be useful in this regard. We investigated the effect of a bezafibrate derivative, RSR-4, on the oxygen affinity of RBCs and purified hemolysates containing HbA and HbH. This allosteric effector crosses RBC membranes and binds reversibly to the alpha-chains of deoxy-Hb, decreasing hemoglobin oxygen affinity. The blood used was obtained from a patient with HbH disease (alphaTSaudi homozygote) whose HbH level was 33.5% as measured by high-performance liquid chromatography. Oxygen binding studies were performed in RBCs and purified hemolysates. RBCs incubated in the presence of 500 microM RSR-4 (2-[[[(3,5-dichloroanilino)-carbonyl]methyl]phenoxy]-2-methylpropi onic acid) in standard conditions (pH 7.4, 0.14 M NaCl, 37 degrees C) displayed an increase in their P50 value from 14.5 to 35.2 mm Hg. Oxygen binding studies in purified stripped hemolysates (pH 7.2, 0.1 M NaCl, 25 degrees C) showed that addition of both 500 microM RSR-4 and 1 mM of 2,3 diphosphoglycerate (DPG) led to an 11-fold decrease in oxygen affinity, whereas the addition of the natural effector DPG or RSR-4 alone produced a 2.7- and 5.7-fold decrease, respectively. In both cases, the oxygen equilibrium curves (OECs) were biphasic due to the presence of the noncooperative, high-oxygen-affinity HbH (beta4) component. After addition of RSR-4, the lower part of the OEC (corresponding to HbH) was not shifted compared with the upper part (corresponding to HbA). These results were confirmed by kinetic studies of CO recombination. Both experiments demonstrated that RSR-4 does not affect beta4 Hb. Our findings provide an experimental model for lowering the oxygen affinity of HbA in HbH-containing cells and suggest that the oxygen delivery capability of the latter would be thereby improved.

Allosteric Regulation↗
PubMed1998

Involvement of donor T-cell cytotoxic effector mechanisms in preventing allogeneic marrow graft rejection.

Donor CD8 cells play a pivotal role in preventing allogeneic marrow graft rejection, possibly by generating cytotoxic effectors needed to eliminate recipient T cells remaining after the pretransplant conditioning regimen or by producing cytokines needed to support the growth and differentiation of hematopoietic stem cells. In the present study, we assessed the role of donor T-cell cytotoxic effector function as a mechanism for eliminating recipient CD8 cells that cause marrow graft rejection in mice. The ability to prevent rejection was minimally affected by the presence of a defect in Fas ligand binding or by the absence of granzyme B but was severely affected by the absence of perforin. Doubly mutant perforin-deficient, Fas ligand-defective CD8 cells were completely unable to prevent rejection. Our results indicate first that recipient CD8 effectors responsible for causing marrow graft rejection are sensitive to cytotoxicity mediated by both perforin- and Fas-ligand-dependent mechanisms, and second that donor T cells must have at least one functional cytotoxic mechanism to prevent allogeneic marrow graft rejection.

Animals↗
PubMed1996

Activation of human effector cells by a tumor reactive recombinant anti-ganglioside GD2 interleukin-2 fusion protein (ch14.18-IL2).

Cytotoxic effector cells interact with target cells through various mechanisms. CTLs use the antigen-specific T cell receptor, whereas Fc receptor-positive natural killer cells use this receptor to interact with antibody-coated target cells. We evaluated the tumor-binding and lymphocyte-activating capability of a recombinant fusion protein consisting of a tumor-selective human/mouse chimeric anti-ganglioside GD2 antibody (ch14.18) and recombinant human interleukin-2 (IL2) (ch14.18-IL2). This fusion protein bound specifically to GD2-positive melanoma and neuroblastoma tumor cell lines, and its IL2 component stimulated in vitro proliferation of an IL2-dependent cell line, as well as peripheral blood mononuclear cells, in healthy control individuals and in cancer patients receiving continuous infusion of IL2. The IL2 presented by the fusion protein, when bound to tumor cells, induced proliferation of IL2-responsive cells as well as a comparable amount of soluble IL2 did. This suggests that localization of IL2 at the site of contact between tumor and effector cells is an effective way of presenting this cytokine to IL2-responsive cells. The ch14.18-IL2 fusion protein also mediated antibody-dependent cellular cytotoxicity with Fc receptor-positive effector cells to an extent similar to ch14.18. These results, together with those of previous studies documenting antitumor efficacy against human tumor xenografts in SCID mice and GD2-positive murine tumors in immunocompetent syngeneic mice, suggest that the ch14.18-IL2 fusion protein should be tested in Phase I and II trials in patients with GD2-positive tumors.

Animals↗
PubMed1999

B7.2 has opposing roles during the activation versus effector stages of experimental autoimmune thyroiditis.

APCs provide costimulatory and down-regulatory signals to Ag-activated T cells through interactions between B7.1 and B7.2 on APCs with either CD28 or CTL Ag-4 expressed on T cells. Recipients of mouse thyroglobulin (MTg)-primed spleen cells activated in the presence of anti-B7.2 had decreased experimental autoimmune thyroiditis (EAT) severity compared with recipients of cells cultured with control rat Ig or anti-B7.1. Blocking B7.2 during in vivo priming also suppressed the ability of MTg-primed spleen cells to transfer EAT, implicating a role for B7.2 for priming and in vitro activation of EAT effector cells. In contrast, administration of anti-B7.2 or anti-B7.2 Fab to recipients of MTg-activated spleen cells increased the severity of EAT compared with recipients receiving control Ig. Thyroids from anti-B7.2-treated recipients had increased expression of IL-4 mRNA compared with thyroids from rat Ig-treated controls. Both B7.1 and B7.2 molecules were expressed in the thyroids of mice with EAT, although B7.2 was more prevalent than B7.1. Administration of both anti-B7.1 and anti-B7.2 to recipient mice suppressed the development of EAT, while anti-B7.1 treatment alone had no effect on EAT severity. The suppression of EAT was not observed when anti-B7.1 and anti-B7.2 treatment was delayed until 7 days after cell transfer, suggesting a requirement for B7 in the initiation of EAT in recipient mice. These results suggest that costimulation is required during the effector phase of EAT and that B7.2 may have opposing roles in the activation versus effector stages of autoreactive T cells.

Abatacept↗
PubMed2024

A gene with a thousand alleles: The hyper-variable effectors of plant-parasitic nematodes.

Pathogens are engaged in a fierce evolutionary arms race with their host. The genes at the forefront of the engagement between kingdoms are often part of diverse and highly mutable gene families. Even in this context, we discovered unprecedented variation in the hyper-variable (HYP) effectors of plant-parasitic nematodes. HYP effectors are single-gene loci that potentially harbor thousands of alleles. Alleles vary in the organization, as well as the number, of motifs within a central hyper-variable domain (HVD). We dramatically expand the HYP repertoire of two plant-parasitic nematodes and define distinct species-specific "rules" underlying the apparently flawless genetic rearrangements. Finally, by analyzing the HYPs in 68 individual nematodes, we unexpectedly found that despite the huge number of alleles, most individuals are germline homozygous. These data support a mechanism of programmed genetic variation, termed HVD editing, where alterations are locus specific, strictly governed by rules, and theoretically produce thousands of variants without errors.

Animals↗
PubMed2001

Molecular secrets of bacterial type III effector proteins.

Most Gram-negative phytopathogenic bacteria are thought to inject effector proteins into the plant cell via a type III secretion system that is essential for pathogenicity. Plant targets and the mode of action of type III effector proteins, which include avirulence (Avr) proteins, are largely unknown. However, recent findings have shed light on the molecular mechanisms of Avr action. Here, we focus on two classes of Avr proteins (the AvrBs3 and AvrRxv/YopJ families) that have been suggested to act as transcription factors and proteases, respectively.

Apoptosis↗
PubMed2002

Getting across--bacterial type III effector proteins on their way to the plant cell.

Pathogenicity of most Gram-negative bacterial plant pathogens depends on hrp (hypersensitive response and pathogenicity) genes, which control the ability to cause disease and to elicit specific defense responses in resistant plants. hrp genes encode a specialized type III secretion (TTS) system that mediates the vectorial delivery of bacterial effector proteins across both bacterial membranes as well as across the eukaryotic plasma membrane into the host cell cytosol. One well-studied effector protein is AvrBs3 from Xanthomonas campestris pv. vesicatoria, the causal agent of bacterial spot in pepper and tomato. AvrBs3 induces hypertrophy symptoms in susceptible plants and triggers a resistance gene-specific cell death reaction in resistant plants. Intriguingly, AvrBs3 has characteristic features of eukaryotic transcription factors, suggesting that it modulates the host's transcriptome. Here, we discuss the TTS system of X.campestris pv. vesicatoria in the light of current knowledge on type III-dependent protein secretion in plant pathogenic bacteria.

Bacteria↗
PubMed2001

Macrophage effector mechanisms in melanoma in an experimental study.

BACKGROUND: The tumor-bearing state is known to induce immune dysfunction that contributes to increased infectious complications and tumor progression. However, the mechanisms underlying this immunosuppression remain unclear. HYPOTHESIS: Macrophage (MO) dysfunction may play a role in tumor-induced immunosuppression. DESIGN AND MAIN OUTCOME MEASURES: Using a murine model, this study investigated the effects of melanoma growth on peritoneal macrophage effector molecule and prostaglandin production, MO-mediated cytotoxicity, and candidacidal mechanisms. Female C57BL/6 mice were inoculated with 106 B16 melanoma cells or a salt solution subcutaneously. Mice were euthanized 3 weeks later and peritoneal MOs were harvested and assayed for nitric oxide, superoxide anion, tumor necrosis factor alpha, and prostaglandin E(2)production. Macrophage-mediated cytotoxicity against B16 melanoma targets and MO candidacidal mechanisms were also measured. RESULTS: Macrophage production of nitric oxide, superoxide anion, and tumor necrosis factor alpha were significantly decreased, while prostaglandin E(2)production was increased in MOs from melanoma-bearing mice. Concomitantly, MO-mediated cytotoxicity and candidacidal mechanisms were significantly impaired. CONCLUSIONS: Melanoma growth leads to decreased MO effector molecule production, increased prostaglandin E(2)production, and impaired MO cytotoxic and candidacidal mechanisms. These results may help explain the observed increased infectious complications in the tumor-bearing host. Strategies aimed at restoring MO function may have therapeutic potential.

Animals↗
PubMed1996

Cis-diamminedichloroplatinum(II) augments expression of tumor-associated antigens on human gastric cancer cell line KATO-3 and increases susceptibility and binding of tumor cells to various cytotoxic effector cells.

Previous studies have demonstrated the immunomodulatory effects of cisplatin under certain conditions. The present study was designed to clarify whether cisplatin modulates the expression of surface antigens, especially human leukocyte antigen (HLA), on human tumor cell lines and/or augments the susceptibility and binding of tumor cells to cytotoxic effector cells. A human gastric cancer cell line, KATO-3, was employed. The expression of HLA and other tumor-associated antigens was analyzed by flow cytometry using FITC-conjugated monoclonal antibodies. The cytotoxicity of effector cells was determined by 51Cr release assay. The expression of HLA class I antigen, beta2-microglobulin, leukocyte function-associated antigen-1, and AC-81 adenocarcinoma-associated antigen on KATO-3 increased after exposure to cisplatin at 10 micrograms/ml for 3-6 hr; augmentation of HLA class I subtypes -B2 and -B27 was particularly prominent. Furthermore, the susceptibility and binding of KATO-3 to both lymphokine-activated killer cells and KATO-3-specific cytotoxic T lymphocytes significantly increased after cisplatin treatment. Cisplatin may modulate the expression of tumor-associated antigens on some human tumor cells. Tumor regression by cisplatin administration may depend on its direct cytotoxicity as well as on its modulating effects on the expression of tumor-associated antigens, subsequently leading to the activation of the immune surveillance system against the tumor.

Adjuvants, Immunologic↗
PubMed1997

Human gastric carcinoma transduced with the IL-2 gene: increased sensitivity to immune effector cells in vitro and in vivo.

We transduced a human gastric carcinoma cell line, HR, with the interleukin 2 (IL-2) gene. Stable HR transfectants secreted nanogram quantities of biologically active IL-2 and had significantly increased expression of IL-2 mRNA relative to that in parental cells. Expression of intracellular IL-2 protein was not quantitatively different in the parental and IL-2 gene-transduced cells, although the former did not secrete IL-2. Surface expression of IL-2 receptors was comparable in the parental and transduced cells at the mRNA or protein levels. Nevertheless, in vitro proliferation of IL-2 gene-transduced HR cells was significantly more rapid than that of parental cells. Both parental and IL-2 gene-transduced HR cells were equally sensitive to lysis by IL-2-activated natural killer (A-NK) cells, as measured in 4 hr 51Cr-release assasys or to apoptosis induced by NK or A-NK cells, assessed in 1 hr 3H-TdR-release assays. In 24 hr MTT assays, however, the IL-2 gene-transduced cells were significantly more sensitive to these effector cells than were parental cells. Upon intrasplenic injection of 5 x 10(6) parental or transduced HR cells into nude mice, liver metastases developed. Metastases of parental HR cells killed the animals in 24 days. In contrast, metastases of the IL-2 gene-transduced HR cells became necrotic by day 14 and were found to be surrounded by murine NK cells and macrophages. Survival of nude mice injected with IL-2 gene-transduced HR cells was significantly prolonged (>50 days) relative to that of mice injected with parental HR. Thus, IL-2 gene-transduced HR cells produced sufficient amounts of functional IL-2 in vivo to be able to recruit to the tumor site and support functions of endogenous cytotoxic immune effector cells, which were responsible for regression of hepatic metastases and significant improvement of survival in these mice.

Animals↗
PubMed1996

ras effector loop mutations that dissociate p120GAP and neurofibromin interactions.

ras proteins are positively regulated by nucleotide exchange factors and negatively regulated by GTPase-activating proteins (GAPs). Two GAPs have been found in mammalian cells, p120GAP and neurofibromin, the product of the type 1 neurofibromatosis (NF1) gene. A library of substitutions in the effector loop region of ras in an Escherichia coli plasmid expression system was screened for c-Ha-ras species with altered GAP interactions. Several substitutions preferentially disrupted the interaction of ras with p120GAP as compared with the interaction with the recombinant GAP-related domain of neurofibromin (NF1-GRD). The most extreme example, Tyr32His, encoded a ras species that was unaffected by p120GAP but was stimulated normally by NF1-GRD. Tyr32His was weakly transforming in Rat2 cells. Tyr32His ras was primarily GDP-bound in quiescent Rat2 cells, although it rapidly associated with GTP after treatment of cells with epidermal growth factor. These results show that the NF1 product has less stringent requirements than p120GAP for ras effector domain structure and that negative regulation of ras can be achieved in rat fibroblasts by the product of NF1.

Animals↗
PubMed1998

Human memory T cell differentiation into Th2-like effector cells is dependent on IL-4 and CD28 stimulation and inhibited by TCR ligation.

Freshly isolated memory T cells primarily produced IL-2 and small amounts of IL-4 and IFN-gamma after stimulation in vitro. Priming for 5 days in vitro with anti-CD28 monoclonal antibodies (mAb) alone markedly increased production of IL-4. In comparison to fresh cells, the increase in the amount of IL-4 secreted reflected a marked increase in the number of IL-4-producing cells. Stimulation with immobilized anti-CD3 mAb during priming limited subsequent IL-4 production. By contrast, IFN-gamma production from in vitro primed memory T cells was directly correlated to the concentration of priming anti-CD3 mAb. IL-2 production by all restimulated cells was decreased. The differentiation of IL-4-producing cells could be blocked by antibody to IL-4 and enhanced by the addition of recombinant IL-4 as well as antibody to IFN-gamma. Of note, the IL-4-producing effector cells induced from in vitro priming derived from the early CD27pos memory T cell subset, whereas the small CD27neg differentiated memory subset produced IL-4 without in vitro priming. The results indicate that memory T cells can be directed to differentiate into IL-4-producing effector cells by stimulation via CD28 and IL-4, whereas increasing engagement of the TCR limits Th2 memory cell differentiation.

Antibodies, Monoclonal↗