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At least 19 recordsLinked to original sources
PubMed1982

Effect of interleukin 2 on cytotoxic effectors: I. Short-term culture of the cytotoxic effectors and the in vivo anti-tumor activity of the cultured effectors isolated from tumor site.

The effects of interleukin 2 (IL2) on the in vitro and in vivo activity of cytotoxic T cells have been studied. IL2 was produced by W/Fu rat spleen cells cultured with concanavalin A. The IL2 thus prepared gave an optimal T-cell growth-promoting effect at a concentration of 5-20% equivalents of the original preparation. In the primary syngeneic mixed lymphocyte/tumor cell cultures (MLTC) against FBL-3 tumor cells, the addition of IL2 failed to generate a cytotoxic response. However, the cytotoxic response could be generated in MLTC by addition of exogenous macrophages. On the other hand, IL2 could maintain the growth of performed cytotoxic T cells for 3 to 5 weeks. These cytotoxic T cells were generated either by in vitro sensitization (MLC or MLTC) or by in vivo sensitization of B6 mice against a syngeneic tumor FBL-3. In short-term cultures, augmentation of the cytotoxic activity was seen after 10 days' culturing with IL2. The antigenic specificity of the cytotoxic reaction was altered after 28-35 days in culture, and the effectors broadly reactive. When growing a nonadherent population of lymphocytes isolated from FBL-3 ascites tumor, supplementation with IL2 selectively promoted the growth of a T-cell population, resulting in the elimination of the contaminating tumor cells. These purified T cells were highly cytotoxic for FBL-3 cells in vitro and also possessed strong in vivo anti-tumor activity against FBL-3 cells in the adoptive transfer experiments. The present study demonstrates that short-term culture (2-3 weeks) in IL2 promotes the growth of T cells and augments their cytotoxic activity with the appropriate antigenic specificity. IL2 also promoted the selective growth of T cells isolated from tumor site and these T cells showed augmented in vitro and in vivo anti-tumor activity.

Animals↗
PubMed1995

Control of CD4 effector fate: transforming growth factor beta 1 and interleukin 2 synergize to prevent apoptosis and promote effector expansion.

The signals that determine the size and duration of the primary T cell immune response are not well defined. We studied CD4 T cells at an important checkpoint in their development: when they have become effectors and are ready to rapidly mediate effector functions, both via direct interaction with antigen (Ag)-presenting cells and via cytokine production. We determined the effects of specific Ag and the cytokines interleukin (IL) 2 and transforming growth factor (TGF) beta 1 on T helper cell type 2 (Th2) effector apoptosis versus expansion. Th2-polarized effector cells were generated in vitro from naive CD4 T of T cell receptor transgenic mice, and then restimulated with or without peptide Ag plus Ag-presenting cells and cytokines. In the absence of added cytokines, effector cells cultured without Ag died of apoptosis after 4-7 d. Paradoxically, Ag both induced proliferation and high levels of cytokine synthesis and accelerated effector cell death. IL-2 directly induced proliferation of effectors, supported and prolonged Ag-induced proliferation, and partially blocked apoptosis. TGF-beta did not effect proliferation or influence cytokine secretion, but it also partially blocked apoptosis. Together, IL-2 and TGF-beta synergized to almost completely block apoptosis, resulting in prolonged effector expansion and leading to the accumulation of a large pool of specific effectors. When Ag and both cytokines were present, the effector population increased 10(4)-10(5) fold over 20 d of culture. The synergy of IL-2 and TGF-beta suggests that they interfere with programmed cell death by distinct mechanisms. Since Th2 effectors are specialized to help B cells develop into antibody-secreting plasma cells, these results suggest that the availability of Ag and of the cytokines IL-2 and TGF-beta is a key factor influencing the fate of Th2 effector cells and thus the size and duration of the primary antibody response.

Animals↗
PubMed1999

Effector CD4 T cells are biochemically distinct from the memory subset: evidence for long-term persistence of effectors in vivo.

Memory T cell responses are believed to be mediated by long-lived memory T cells that arise directly from a subset of short-lived, activated effector T cells that have reverted to the resting state. Although widely accepted, definitive proof that memory T cells arise from effectors is lacking because of the inability to reliably distinguish these subsets based on known phenotypic or functional parameters. We have used a biochemical approach to distinguish effector and memory CD4 T cell subsets and follow the differentiative fate of effector cells in vivo. When examined biochemically, effector and memory CD4 T cells are strikingly distinct and exhibit qualitative and quantitative differences in tyrosine phosphorylation. These effector-specific patterns were identical in effectors derived either from naive CD4 T cells (primary effectors) or memory CD4 T cells (memory effectors). To monitor the fate of effector cells in vivo, Ag-activated CD4+ TCR-transgenic T cells were transferred into irradiated BALB/c mice. These TCR-transgenic CD4 T cells persisted in adoptive hosts for several months, gave a recall response to Ag, yet exhibited effector-specific biochemical profiles. These results suggest that a subset of effector CD4 T cells can persist in vivo and contribute to long-term immunity by mediating secondary immune responses.

Adoptive Transfer↗
PubMed1989

Kinetic analysis of effector cell recycling and effector-target binding capacity in a model of cell-mediated cytotoxicity.

A kinetic analysis of cell-mediated cytotoxicity (CMC) at the population level based on theoretical models has been performed. This analysis considers that the binding process and the kinetics of the lytic process occur through different types of conjugates: LTn, i.e., conjugates containing one effector cell and n target cells, and LmT conjugates which contain m effector cells bound to one target cell. This allowed us to provide a quantitative description of the conjugation process, and of the binding capacities of the effector and target cells. Thus, it has been shown that these processes are governed by an equilibrium in which are involved the unbound effector and target cells, and the conjugates formed. This implies that, when the equilibrium concentrations are reached, the total number of conjugates cannot be increased from the unbound effector and target cells. However, it does not mean that the free effector cells are nonbinding, and so, when the conditions of equilibrium are perturbated (as occurs for example in CMC), all effector cells, virgin and those who have already participated in the lytic process, are able to form new conjugates. The existence of this equilibrium has also important consequences when different subpopulations are separated from an effector-target system. Thus, it explains the observation reported in the literature that, although cytometric techniques can be used to detect and count different types of conjugates, the conjugates formed cannot be separated by cell sorting (unless special precautions are taken). Finally, we have found that the number of target cells killed by one effector cell, which has been previously considered as the recycling capacity of an effector population, is in reality the result of two different mechanisms. One of these mechanisms is due to the recycling process, whereas the other (which has the same effect) is due to the multiple killing capacity of the LTn conjugates which kill more than one target cell. The average number of target cells killed per conjugate has been determined, and this allowed us to obtain the relative contributions of these two mechanisms to the total killing capacity of one effector cell. It appears that the recycling capacities of effector cell populations previously determined had been 1- to 3-fold overestimated.

Animals↗
PubMed1998

Selective inhibition of Ras interaction with its particular effector by synthetic peptides corresponding to the Ras effector region.

Ras proteins possess multiple downstream effectors of distinct structures. We and others demonstrated that Ha-Ras carrying certain effector region mutations could interact differentially with its effectors, implying that significant differences exist in their Ras recognition mechanisms. Here, by employing the fluorescence polarization method, we measured the activity of effector region synthetic peptides bearing various amino acid substitutions to inhibit association of Ras with the effectors human Raf-1 and Schizosaccharomyces pombe Byr2. The effect of these peptides on association with another effector Saccharomyces cerevisiae adenylyl cyclase was also examined by measuring inhibition of the Ras-dependent adenylyl cyclase activity. The peptide corresponding to the residues 17-44 competitively inhibited Ras association with all the three effectors at the Ki values of 1 approximately 10 microM, and the inhibition was considerably attenuated by the D38A mutation. The peptide with the D38N mutation inhibited association of Ha-Ras with Byr2 but not with the others, whereas that with the P34G mutation inhibited association of Ha-Ras with Raf-1 and Byr2 but not with adenylyl cyclase. Thus, the specificity observed with the whole Ras protein was retained in the effector region peptide. These results suggest that the effector region residues constitute a major determinant for differential recognition of the effector molecules, raising a possibility for selective inhibition of a particular Ras function.

Adenylyl Cyclases↗
PubMed1995

Stimulation of inositol 1,4,5-trisphosphate production by peptides corresponding to the effector domain of different Rab3 isoforms and cross-linking of an effector domain peptide target.

Rab3 proteins are localized on secretory vesicles and appear to be involved in regulated exocytosis. We have previously shown that a modified peptide corresponding to the effector domain of the small molecular mass GTP-binding protein Rab3A, Rab3AAL, stimulates inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] production and amylase release in digitonin-permeabilized pancreatic acini. Experiments using monoclonal antibodies reveal that the Rab3-like protein present in pancreatic acini is not the Rab3A isoform. However, since the putative effector domains of the four as yet known Rab3 proteins (A, B, C and D) differ only in the C-terminal four amino acid residues, Rab3A effector domain peptide could mimic the action of the pancreas-specific Rab3 isoform. In the present study we report that peptides corresponding to the different Rab3 isoforms stimulate both Ins(1,4,5)P3 production and amylase secretion with an order of potency Rab3B/D > Rab3AAL > Rab3A = Rab3C. For Rab3A, B/D and C effector domain peptides the concentrations causing half-maximal response (EC50) were 3, 0.2 and 3 nM for Ins(1,4,5)P3 accumulation and 0.3, 0.02 and 0.3 nM for amylase release, respectively. A Rab1A effector domain peptide, Rab1AAL, and a scrambled peptide of Rab3AAL were less potent by several orders of magnitude in eliciting these responses compared with native Rab3 effector domain peptides. None of the peptides influenced Ins(1,4,5)P3 production and amylase release in intact acini. Cross-linking of 125I-Rab3B/D peptide to pancreatic acinar membranes showed a band at 70 to 75 kDa with maximum intensity at 75 kDa. Radiolabelling of the substrates could be displaced by unlabelled Rab3B/D peptide, and to a lesser extend by Rab3A peptide, whereas the scrambled peptide of Rab3AAL had no effect. These data suggest that phospholipase C and exocytosis might be regulated by Rab3B-or Rab3D-like proteins in pancreatic acinar cells. A 75 kDa protein that preferentially cross-linked to 125I-Rab3B/D effector domain peptide is a potential candidate as an effector protein of Rab3 effector domain peptides.

Amino Acid Sequence↗
PubMed1999

Interference between effector RNAs expressed from conventional dual-function anti-HIV retroviral vectors can be circumvented using dual-effector-cassette retroviral vectors.

Coexpression of different effector molecules from a single vector (a dual-function vector) may provide enhanced efficacy. Thus far most of the reported anti-HIV dual-function vectors express different effector RNAs as a chimeric molecule. In our study involving retroviral vectors coexpressing a U5 ribozyme and either an anti-tat or anti-rev antisense RNA, chimeric vectors exhibit poor potency in several important functional aspects, including inhibition of HIV replication, protection against cytopathic effects, and suppression of target gene function. Surprisingly, such a poor efficacy of chimeric vector function was not associated with a lower level of effector RNA expression. These results indicate that expression of two effector RNAs as a chimeric molecule can lead to interference, reducing their global biological effects. More importantly, we have demonstrated that such interference can be avoided by coexpressing these effector RNAs as separate molecules through a new dual-function vector, called a dual-effector cassette (Dec) vector, developed in this study. We also define some of the design alterations that might affect the efficacy of the Dec vector and demonstrate that forward-designed Dec vectors are more efficacious than reverse-designed Dec vectors, which express a lower level of effector RNA owing to the instability of the 5' effector cassettes in the provirus. We believe that the principle of Dec vector design may also be applicable for the coexpression of other therapeutic RNA effectors in many gene therapy applications.

Cell Line↗
PubMed1998

RhoA effector mutants reveal distinct effector pathways for cytoskeletal reorganization, SRF activation and transformation.

The RhoA GTPase regulates diverse cellular processes including cytoskeletal reorganization, transcription and transformation. Although many different potential RhoA effectors have been identified, including two families of protein kinases, their roles in RhoA-regulated events remain unclear. We used a genetic screen to identify mutations at positions 37-42 in the RhoA effector loop that selectively disrupt effector binding, and used these to investigate the role of RhoA effectors in the formation of actin stress fibres, activation of transcription by serum response factor (SRF) and transformation. Interaction with the ROCK kinase and at least one other unidentified effector is required for stress fibre formation. Signalling to SRF by RhoA can occur in the absence of RhoA-induced cytoskeletal changes, and did not correlate with binding to any of the effectors tested, indicating that it may be mediated by an unknown effector. Binding to ROCK-I, but not activation of SRF, correlated with the activity of RhoA in transformation. The effector mutants should provide novel approaches for the functional study of RhoA and isolation of effector molecules involved in specific signalling processes.

3T3 Cells↗
PubMed2004

Effector cell-derived lymphotoxin alpha and Fas ligand, but not perforin, promote Tc1 and Tc2 effector cell-mediated tumor therapy in established pulmonary metastases.

Cytolytic CD8(+) effector cells fall into two subpopulations based on cytokine secretion. Type 1 CD8(+) T cells (Tc1) secrete IFN-gamma, whereas type 2 CD8(+) T cells (Tc2) secrete interleukin (IL)-4 and IL-5. Although both effector cell subpopulations display Fas ligand (FasL) and tumor necrosis factor (TNF), tumor lysis is predominantly perforin dependent in vitro. Using an ovalbumin-transfected B16 lung metastasis model, we show that heightened numbers of adoptively transferred ovalbumin-specific Tc1 and Tc2 cells accumulated at the tumor site by day 2 after therapy and induced tumor regression that enhanced survival in mice with pulmonary metastases. Transfer of either TNF-alpha- or perforin-deficient Tc1 or Tc2 effector cells generated from specified gene-deficient mice showed no differences in therapeutic efficiency when compared with corresponding wild-type cells. In contrast, both Tc1 and Tc2 cells, derived from either FasL or TNF-alpha/lymphotoxin (LT) alpha double knockout mice, showed that therapeutic effects were dependent, in part, on effector cell-derived FasL or LTalpha. Six days after effector cell therapy, elevated levels of activated endogenous CD8/CD44(High) and CD4/CD44(High) T cells localized and persisted at sites of tumor growth, whereas donor cell numbers concomitantly decreased. Both Tc1 and Tc2 effector cell subpopulations induced endogenous antitumor responses that were dependent, in part, on recipient-derived IFN-gamma and TNF-alpha. However, neither effector cell-mediated therapy was dependent on recipient-derived perforin, IL-4, IL-5, or nitric oxide. Collectively, tumor antigen-specific Tc1 and Tc2 effector cell-mediated therapy is initially dependent, in part, on effector cell-derived FasL or LTalpha that may subsequently potentiate endogenous recipient-derived type 1 antitumor responses dependent on TNF-alpha and IFN-gamma.

Animals↗
PubMed2005

CesT is a multi-effector chaperone and recruitment factor required for the efficient type III secretion of both LEE- and non-LEE-encoded effectors of enteropathogenic Escherichia coli.

Enteropathogenic Escherichia coli (EPEC) is an intestinal attaching and effacing pathogen that utilizes a type III secretion system (T3SS) for the delivery of effectors into host cells. The chaperone CesT has been shown to bind and stabilize the type III translocated effectors Tir and Map in the bacterial cytoplasm prior to their delivery into host cells. In this study we demonstrate a role for CesT in effector recruitment to the membrane embedded T3SS. CesT-mediated effector recruitment was dependent on the presence of the T3SS membrane-associated ATPase EscN. EPEC DeltacesT carrying a C-terminal CesT variant, CesT(E142G), exhibited normal cytoplasmic Tir stability function, but was less efficient in secreting Tir, further implicating CesT in type III secretion. In vivo co-immunoprecipitation studies using CesT-FLAG containing EPEC lysates demonstrated that CesT interacts with Tir and EscN, consistent with the notion of CesT recruiting Tir to the T3SS. CesT was also shown to be required for the efficient secretion of several type III effectors encoded within and outside the locus of enterocyte effacement (LEE) in addition to Tir and Map. Furthermore, a CesT affinity column was shown to specifically retain multiple effector proteins from EPEC culture supernatants. These findings indicate that CesT is centrally involved in recruiting multiple type III effectors to the T3SS via EscN for efficient secretion, and functionally redefine the role of CesT in multiple type III effector interactions.

Adenosine Triphosphatases↗
PubMed2005

A genome-wide screen identifies a Bordetella type III secretion effector and candidate effectors in other species.

Bordetella bronchiseptica utilizes a type III secretion system (TTSS) for induction of non-apoptotic cytotoxicity in host cells and modulation of host immunity. The identity of Bordetella TTSS effectors, however, has remained elusive. Here we report a genome-wide screen for TTSS effectors based on shared biophysical and functional characteristics of class I chaperones and their frequent colocalization with TTSS effectors. When applied to B. bronchiseptica, the screen identified the first TTSS chaperone-effector locus, btcA-bteA, and we experimentally confirmed its function. Expression of bteA is co-ordinated with expression of TTSS apparatus genes, BteA is secreted through the TTSS of B. bronchiseptica, it is required for cytotoxicity towards mammalian cells, and it is highly conserved in the human-adapted subspecies B. pertussis and B. parapertussis. Transfection of bteA into epithlieal cells results in rapid cell death, indicating that BteA alone is sufficient to induce potent cytotoxicity. Finally, an in vitro interaction between BteA and BtcA was demonstrated. The search for TTSS chaperones and effectors was then expanded to other bacterial genomes, including mammalian and insect pathogens, where we identified a large number of novel candidate chaperones and effectors. Although the majority of putative effectors are proteins of unknown function, several have similarities to eukaryotic protein domains or previously identified effectors from other species.

Bacterial Proteins↗
PubMed1987

Effector T cell differentiation in experimental interstitial nephritis. I. The development and modulation of effector lymphocyte maturation by I-J+ regulatory T cells.

Because mice susceptible to interstitial nephritis use different effector T cells than nonsusceptible mice, we analyzed the differentiation process of the effector T cell repertoire by using an in vitro culture technique. In the presence of helper T lymphocytes, accessory cells, IL 2, tubular antigen, and precursor effector cells, both Lyt-2+ nephritogenic effector cells and L3T4+ nonnephritogenic effector cells can be initially induced in both susceptible and nonsusceptible strains within 3 days of culture. In nonsusceptible mice, however, the Lyt-2+ nephritogenic cell is inhibited from further development and disappears, whereas in susceptible mice, its presence is preserved with a resulting effect of tissue destruction. This selection of effector T cell preference is regulated by I-J+ T lymphocytes which are co-functionally expressed with effector cell expansion. Unlike precursor effector lymphocytes, however, the maturation of the regulatory process requires a subset of I-J+ accessory cells and structurally intact tubular antigen. Our findings indicate, therefore, that both susceptible and nonsusceptible mice have the potential for the expression of interstitial nephritis, but nonsusceptible mice are formally protected from autoimmunity by the regulation of lymphocyte preference.

Animals↗
PubMed1981

T lymphocyte responses to non-H-2 histocompatibility antigens. I. Role of Ly-1+2+ T cells as cytotoxic effectors and requirement for Ly-1+2+ T cells for optimal generation of cytotoxic effectors.

Cytotoxic effector T cells specific for non-H-2 histocompatibility (H) antigens were examined for phenotypic expression of lymphocyte differentiation (Ly) antigens. Virtually all H-Y-specific cytotoxic effectors generated in mixed lymphocyte culture were Ly-1+2+ T cells. H-3-specific effectors comprised both Ly-1+2+ and Ly-1-2+ T cells. However, cytotoxic effectors specific for multiple non-H-2 H antigens were predominantly Ly-1-2+ T cells. The optimal generation of H-Y- and H-3-specific effectors required Ly-1+2+ T cells; optimal generation of multiple non-H-2 H antigen-specific effectors required an interaction between Ly-1+2- and Ly-1-2+ T cells. These observations suggest that the identity of the target H antigen in part determines the Ly type of responsive T cells. Our observations suggest that 2 alternative pathways of T cell response exist for non-H-2 H antigens. The first pathway involves an interaction between Ly-1+2- helper T cells and Ly-1-2+ cytotoxic effector precursors. The 2nd pathway simply involves the response of Ly-1+2+ T cells proliferating and generating H antigen-specific cytotoxic effectors.

Animals↗
PubMed1977

Ribonucleotide reductase from Escherichia coli. Identification of allosteric effector sites by chromatography on immobilized effectors.

Ribonucleotide reductase is responsible for the production of deoxyribonucleotides by catalyzing the reduction of ribonucleoside diphosphates. The enzyme is allosterically regulated in a complex way by the nucleoside triphosphates, ATP, dTTP, dGTP, dCTP, and dATP. Ribonucleotide reductase consists of two nonidentical subunits, proteins B1 and B2. Both substrates and allosteric effectors bind exclusively to B1. Binding of protein B1 to dTTP or dATP covalently coupled to Sepharose and elution with concentration gradients of the different nucleoside triphosphate effectors gave information about (1) the arrangement of the effector binding sites on protein B1 and (2) the affinity of the effectors for these sites. Protein B1 thus has two classes of effector binding sites. One class binds all effectors, as demonstrated by elution of the protein from dTTP-Sepharose with dATP, dGTP, ATP, or dCTP. The second class binds only dATP or ATP, since dATP and ATP were the only nucleotides which eluted protein B1 from dATP-Sepharose. These results confirm earlier data obtained by dialysis binding experiments. The eluting concentrations obtained for the different nucleoside triphosphates in experiments with dTTP-Sepharose could be used to calculate unknown dissociation constants for protein B1 -effector binary complexes. This was possible, since a plot of the eluting concentrations vs. known dissociation constants was linear.

Allosteric Site↗
PubMed2004

Models of the cooperative mechanism for Rho effector recognition: implications for RhoA-mediated effector activation.

Activated GTPases of the Rho family regulate a spectrum of functionally diverse downstream effectors, initiating a network of signal transduction pathways by interaction and activation of effector proteins. Although effectors are defined as proteins that selectively bind the GTP-bound state of the small GTPases, there have been also several indications for a nucleotide-independent binding mode. By characterizing the molecular mechanism of RhoA interaction with its effectors, we have determined the equilibrium dissociation constants of several Rho-binding domains of three different effector proteins (Rhotekin, ROCKI/ROK beta/p160ROCK, PRK1/PKNalpha where ROK is RhoA-binding kinase) for both RhoA.GDP and RhoA.GTP using fluorescence spectroscopy. In addition, we have identified two novel Rho-interacting domains in ROCKI, which bind RhoA with high affinity but not Cdc42 or Rac1. Our results, together with recent structural data, support the notion of multiple effector-binding sites in RhoA and strongly indicate a cooperative binding mechanism for PRK1 and ROCKI that may be the molecular basis of Rho-mediated effector activation.

Amino Acid Sequence↗
PubMed2006

Effector-repressor interactions, binding of a single effector molecule to the operator-bound TtgR homodimer mediates derepression.

The RND family transporter TtgABC and its cognate repressor TtgR from Pseudomonas putida DOT-T1E were both shown to possess multidrug recognition properties. Structurally unrelated molecules such as chloramphenicol, butyl paraben, 1,3-dihydroxynaphthalene, and several flavonoids are substrates of TtgABC and activate pump expression by binding to the TtgR-operator complex. Isothermal titration calorimetry was employed to determine the thermodynamic parameters for the binding of these molecules to TtgR. Dissociation constants were in the range from 1 to 150 microm, the binding stoichiometry was one effector molecule per dimer of TtgR, and the process was driven by favorable enthalpy changes. Although TtgR exhibits a large multidrug binding profile, the plant-derived compounds phloretin and quercetin were shown to bind with the highest affinity (K(D) of around 1 microm), in contrast to other effectors (chloramphenicol and aromatic solvents) for which exhibited a more reduced affinity. Structure-function studies of effectors indicate that the presence of aromatic rings as well as hydroxyl groups are determinants for TtgR binding. The binding of TtgR to its operator DNA does not alter the protein effector profile nor the effector binding stoichiometry. Moreover, we demonstrate here for the first time that the binding of a single effector molecule to the DNA-bound TtgR homodimer induces the dissociation of the repressor-operator complex. This provides important insight into the molecular mechanism of effector-mediated derepression.

Anti-Infective Agents↗
PubMed1997

Unequal death in T helper cell (Th)1 and Th2 effectors: Th1, but not Th2, effectors undergo rapid Fas/FasL-mediated apoptosis.

T helper cell (Th) 1, but not Th2, effectors undergo rapid Fas/Fas ligand (FasL)-mediated, activation-induced cell death upon restimulation with antigen. Unequal apoptosis is also observed without restimulation, after a longer lag period. Both effectors undergo delayed apoptosis induced by a non-Fas-mediated pathway. When Th1 and Th2 effectors are co-cultured, Th2 effectors survive preferentially, suggesting the responsible factor(s) is intrinsic to each population. Both Th1 and Th2 effectors express Fas and FasL, but only Th2 effectors express high levels of FAP-1, a Fas-associated phosphatase that may act to inhibit Fas signaling. The rapid death of Th1 effectors leading to selective Th2 survival provides a novel mechanism for differential regulation of the two subsets.

Animals↗
PubMed1998

Differentiation of naive CTL to effector and memory CTL: correlation of effector function with phenotype and cell division.

Phenotypically and functionally, the early steps of T cell differentiation are not well characterized. In addition, the effector T cell stage shares several phenotypic characteristics with memory T cells, which has made the analysis of T cell memory difficult. In this study, we have investigated in vitro and in vivo the differentiation of naive CTL into effector and memory CTL as a function of cell division using lymphocytic choriomeningitis virus-specific TCR-transgenic spleen cells labeled with the vital dye carboxyfluorescein diacetate, succinimidyl ester. The following major points emerged. 1) During the first nine cell divisions, the investigated cell surface markers were strongly modulated. 2) The TCR was stepwise down-regulated during viral infection. 3) Cytotoxic effector function was acquired within one cell division and was retained during the next four to five divisions. 4) In vitro, CTL reached a CD44highCD62L+ memory phenotype after 6-10 cell divisions and required restimulation to exert effector function. 5) Lymphocytic choriomeningitis virus memory mice contained two distinct memory populations: a CD44highCD62L- population, predominately located in the spleen and exerting rapid effector function, and a CD44highCD62L+ population found in the spleen and the lymph nodes, which had lost immediate effector function. This finding suggests that two types of memory CTL exist. The correlation between CD62L expression, effector function, and Ag persistence is discussed.

Adoptive Transfer↗