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At least 811 records · Page 45Linked to original sources
PubMed2002

Antigen-induced cell death of T effector cells in vitro proceeds via the Fas pathway, requires endogenous interferon-gamma and is independent of perforin and granzymes.

Activation of resting T cells usually leads to their proliferation and differentiation into effector cells and a subsequent decline following elimination of the antigen. A situation of excessive antigen density may result in T cell receptor (TCR)-induced deletion of T effector cells, a process termed antigen-induced cell death (AgICD). Previous studies indicate that AgICD of cytotoxic T cells may be induced by either of the two key cytotoxic processes, granule exocytosis, including perforin and granzymes, or the Fas ligand (FasL)/Fas pathway. By using in vitro-polyclonally activated or ex vivo-derived virus-induced T cell populations from mice with mutations or targeted gene defects in one or more components of the two key cytolytic pathways we now show that TCR-induced apoptosis is only impaired in the absence of FasL and/or Fas, but not in the absence of perforin and/or granzymes. Furthermore, antibody-blockage of FasL alone is sufficient to inhibit early T cell death. Inhibition of both, FasL and tumor necrosis factor (TNF-alpha) is required to abrogate late apoptosis by AgICD. The fact that antibodies to IFN-gamma also inhibit AgICD suggests that the perforin plus granzyme-independent and FaSL and/or TNF-alpha facilitated process of AgICD of T effector cells is tightly regulated by endogenous IFN-gamma.

Animals↗
PubMed1991

Characterization of effector-target conjugates for cloned human natural killer and human lymphokine activated killer cells by flow cytometry.

The present studies demonstrate that the intracellular fluorochromes calcein and hydroethidine can be used for quantification of effector-target conjugates involving cloned human natural killer (NK) or interleukin-2 (IL-2) activated human lymphokine activated killer (LAK) cells by dual color flow cytometry without potential artifacts that might result from extensive modification of effector and/or target cell membranes. Cloned NK cells and LAK cells form conjugates with cultured cell lines regardless of susceptibility to lysis. The strength of the interactions in these conjugates was investigated using a variable speed vortexer. Even relatively gentle vortexing disrupted most conjugates involving fresh human peripheral blood lymphocytes (PBL) but only about one-fourth of conjugates between K-562 cells and human PBL that had been cultured with or without IL-2 by this treatment. The rate of conjugate formation for LAK cells was determined to be about 3 times faster than for cloned NK cells, and both rates are considerably faster than the reported rate of formation of cytotoxic T lymphocyte (CTL) target conjugates. The differences in the rate of conjugate formation are apparently not related to target cell specificity, since LAK cells form conjugates with susceptible and resistant cell lines at comparable rates. When effector-target conjugates are incubated at 37 degrees C in the absence of calcium--thereby precluding lysis--the percentage of conjugated LAK or cloned NK cells decreases logarithmically with time. These results suggest that an initial equilibrium between free and conjugated lymphocytes gradually shifts in favor of unconjugated cells.

Cell Communication↗
PubMed2003

Cell-mediated cytotoxicity evaluation using monoclonal antibody staining for target or effector cells with annexinV/propidium iodide colabeling by fluorosphere-adjusted counts on three-color flow cytometry.

BACKGROUND: In addition to (51)chromium release assay, flow cytometric methods have been described to assess in vitro cell-mediated cytotoxicity. In this report, we describe a new flow cytometric approach for determination of in vitro cell-mediated cytotoxicity utilizing three-color flow cytometric assay. METHODS: This method is based on monoclonal antibody staining of either effector or target cells to evaluate cytotoxicity with increased accuracy by utilizing fluorospheres for calibration. The basic strategy involves labeling effector or target cells with a specific fluorescent-conjugated monoclonal antibody, in addition to staining with annexinV-FITC and propidium iodide to identify apoptotic/dead cells. The effector and target cell populations as well as conjugates were clearly and easily identified by this approach. RESULTS: We obtained significant correlation between cytotoxicity calculated by this technique and (51)chromium release assay results. The integration of fluorospheres allowed us to determine the absolute number of events reflective of the cumulative cell death rather than a cross-sectional, percentage-based cytotoxicity assessment in the target cell population at the time of analysis. CONCLUSIONS: This method provides additional advantages to other methods and enables the study of target cell fate in more detail, as well as providing a potential contribution to understanding the mechanisms of cell elimination.

Annexin A5↗
PubMed1977

The importance of serologically detectable histocompatibility antigens in the induction and effector step of cell-mediated lysis.

The induction and effector steps of T cell-mediated cytotoxicity (CMC) have been studied using a mouse tumor cell line and its variant, which is deficient in serologically defined (SD) H-2 antigens. In allogeneic mice the SDxcell line induces CMC, while the SD- cell line does not. However, both cell lines can be lysed by xenogeneic rat lymphocytes. Antiserum specific for rat T cells was used to demonstrate that CMC of both targetss is partially due to T cells. In allogeneic or syngeneic mouse systems the SD- cells coupled with the 2,4,6-trinitrophenyl (TNP) residue can neither induce CMC nor serve as targets for CMC, while TNP-coupled SDxcells can serve both as immunogen and as targets. Thus allogeneic or syngeneic mouse T cells do not interact with the TNP group of targets lacking H-2 SD antigens. However, mouse T killer cells sensitized to TNP-coupled cells may lyse TNP-coupled targets carrying different H-2 haplotypes. These experiments show that the induction and effector steps of CMC executed by mouse T cells, using TNP-coupled cells as immunogen or targets, need not necessarily demonstrate restriction with regard to a certain genetically defined H-2 haplotype. The presence of cell surface H-2 SD antigens is however, absolutely necessary for the induction and effector steps of CMC by mouse T cells. Using cold target inhibition assays, it was not possible to demonstrate recognition of the TNP moiety on TNP-coupled SDxcells.

Animals↗
PubMed1979

Antibody-dependent cellular cytotoxicity against tumor cells. II. The promonocyte identified as effector cell.

Macrophage precursor cells were cultured from the bone marrow of mice in a liquid culture system in the presence of conditioned medium. To separate their different maturation stages, they were passed through a discontinuous Ficoll density gradient, treated with iron plus magnet or passed through glass bead columns. The different maturation stages have been tested for their function in antibody-dependent cellular cytotoxicity (ADCC) against tumor target cells and in lymphokine-induced macrophage-mediated cytotoxicity. It is shown that the promonocyte, a nonadherent, nonphagocytic precursor cell, is a highly potent cytotoxic effector cell against antibody-coated tumor targets but is totally inactive as an effector cell in lymphokine-induced macrophage-mediated cytotoxicity. In contrast, in the lymphokine-induced macrophage-mediated cytotoxicity the cytotoxic effector cell is a mature macrophage. Thus, ADCC seems to be a function of the macrophage precursor promonocytes, whereas lymphokine-induced cytotoxicity is performed by mature macrophages. The relationship of promonocytes and killer (k) cells in ADCC against tumor targets is discussed.

Animals↗
PubMed1981

Regulation of experimental allergic encephalomyelitis. III. Demonstration of effector cells in tolerant rats.

Effector cells, which transfer experimental allergic encephalomyelitis (EAE), can be demonstrated in the spleens of Lewis rats which have been rendered tolerant to myelin basic protein (BP). Transfer of EAE was achieved following in vitro culture of tolerant donor spleen cells with antigen. The donor animals were, themselves, protected against EAE induced by active challenge with BP in complete Freund's adjuvant, although BP-activated effector spleen cells could partially override this protection. The finding that effector cells are present in unresponsive animals supports the hypothesis that immunologic self tolerance is actively regulated by suppressor mechanisms.

Animals↗
PubMed1981

Influence of IgG and IgM receptor triggering on human natural killer cell cytotoxicity measured on the level of the single effector cell.

By using an agarose single cell cytotoxicity assay, in combination with rosetting with IgG- or IgM-coated ox red blood cells for detection of Fc receptors for IgG (Fc gamma R) or IgM (Fc muR), it was found that 60% of natural killer (NK) cells are Fc gamma R+ and 17% FcmuR+. This system was further used to investigate the consequence of FcmuR and FC gamma R triggering on NK killing as measured on the single effector cell level. It was found that stimulation of the Fc gamma R, but not the FCmuR, resulted in substantial NK inhibition. In order for NK cells to be inhibited by IgG-coated ox red blood cells, they must first be exposed to the IgG-containing complex prior to conjugation with the target. While exposure of the Fc gamma R to immune complexes can block up to 57% of NK activity, the particulate immune complexes do not interfere with binding of effector cells to targets. Modulation of Fc gamma R by capping at 37 degrees C does not interfere with the NK inhibition for up to 3 h, though after 20 h, when Fc gamma R+ cells are almost completely modulated, NK activity has fully returned. Although to a lesser extent, the soluble immune complex human transferrin-anti-transferrin also reduces NK cell activity when activating effector cell FC gamma R prior to target cell binding. Also, pretreatment of target cells with high concentrations of specific antibody toward membrane antigens can block NK activity while not inhibiting target cell binding as evidenced by anti-IgM IgG binding to Daudi cells. The regulatory influence of the Fc gamma R on the NK system is discussed in terms of other functions associated with this receptor and in terms of its possible biological significance.

Animals↗
PubMed1993

Effects of intrathymic injection of organ-specific autoantigens, parietal cells, at the neonatal stage on autoreactive effector and suppressor T cell precursors.

Thymectomy on day 3 after birth (3d-Tx) induces autoimmune gastritis (AIG) in 81%, and oophoritis (AIO) in 25% of BALB/c mice at the age of 2 to 3 months. Intrathymic, but not intraperitoneal injection of syngeneic parietal cells into sex-matched BALB/c mice within 24 h of birth resulted in almost complete prevention of the development of AIG in these mice in which 3d-Tx was performed. The prevention induced was parietal cell specific, since the development of AIO was not inhibited in female mice. Moreover, the injection of BALB/c liver cells, Mls-matched (BALB/c) and -disparate (DBA/2) B blasts which resulted in V beta 6 T cell deletion, as well as the injection of staphylococcal enterotoxin B failed to prevent the diseases. These findings suggested that recognition of an autoantigen in the thymus is necessary for the induction of tolerance, and that involvement of Mls-1 antigens in the pathogenesis of AIG, as has been suggested previously (Schwartz, R. H., Cell 1989. 57: 1073), was unlikely. T cells that suppress the development of organ-specific autoimmune diseases in 3d-Tx mice seem to maintain the unresponsiveness of autoreactive T cells at the periphery in normal mice. In agreement with our previous observations, we found that intraperitoneal (i.p.) injection of spleen cells from 3-month-old normal mice into 3d-Tx mice on day 10 after birth prevented the development of AIG, whereas spleen cells from age-matched AIG+ (mice with AIG) or AIG- (mice without AIG) 3d-Tx mice failed to do this. This implies that the suppressor cells probably affect the differentiation of effector-precursor to effector. In fact, these suppressor cells did not inhibit the adoptive transfer of AIG to nu/nu BALB/c mice by spleen cells from 3d-Tx mice manifesting AIG. By negative selection using monoclonal antibody and complement, it was confirmed that the phenotype of the suppressor cell was CD4. In contrast to 3d-Tx, 10d-Tx did not induce AIG, indicating the peripheralization of the suppressor cell by that time. On the other hand, intrathymic injection of parietal cells immediately after birth did not affect suppressor cell generation, implying that some T cells, including suppressor cells, escape thymus selection. We postulate that these cells correspond to the precursors of the autoreactive effector T cells and suppressor T cells that are present in normal mice.

Animals↗
PubMed2003

Dominant effector memory characteristics, capacity for dynamic adaptive expansion, and sex bias in the innate Valpha24 NKT cell compartment.

Valpha24 natural killer T (NKT) cells are innate immune cells that recognize self and nonself glycolipids presented by CD1d molecules, and play immunoregulatory roles in autoimmunity and tumor immunity. We have investigated the circulating Valpha24 NKT cells in a large cohort of human subjects. CCR7(-) CD45RO(+) effector memory cells dominated both CD4(+) and CD4() NKT subsets, while a minority displayed a central memory phenotype. CD4(-) central memory NKT cells, however, were atypical in that they largely lacked CD62L expression. Overall, CD4(-) NKT cells displayed a functional phenotype with effector characteristics, while the CD4(+) subset appeared immunoregulatory. Interestingly, NKT cell numbers in blood varied widely between subjects, and elevated numbers of these cells were much more common in women than in men. The CD4(+) subset dominated the NKT cell compartment in both sexes, while circulating NKT cell numbers above 0.1% were associated with an expanded CD4(-) subset. Although NKT cell numbers were generally stable over time, we describe a dynamic fivefold expansion that was associated with a skewing of the NKT CD4(+):CD4(-) ratio that persisted after numbers returned to base line. Thus, the two NKT cell subsets display different properties and dynamics that will influence their function as innate immunoregulatory and effector cells.

CD4 Antigens↗
PubMed2004

Phenotypic classification of human CD8+ T cells reflecting their function: inverse correlation between quantitative expression of CD27 and cytotoxic effector function.

Phenotypic classification of human CD8(+) T cells using three cell surface markers, CD27, CD28 and CD45RA, was recently suggested to be useful for identification of naive, memory and effector CD8(+) T cells. However, it still remains unclear whether such classification precisely reflects functional classification of CD8(+) T cells. To clarify this, we characterized each CD27CD28CD45RA subset of total and human cytomegalovirus (HCMV)-specific CD8(+) T cells by analyzing the expression of perforin and two chemokine receptors, CCR5 and CCR7, as well as their function. An inverse correlation between perforin and CD27 expression was found in all four CD28CD45RA subsets. Therefore, to achieve a phenotypic classification of CD8(+) T cells that more precisely reflects their function, the CD27(+) subset was divided into CD27(low) and CD27(high) subsets based on the expression level of CD27. Functional and flow cytometric analyses of CD27CD28CD45RA subsets showed that this phenotypic classification reflects functional classification of CD8(+) T cells. HCMV-specific CD8(+) T cells from healthy HCMV-seropositive individuals were predominantly found in effector and memory/effector subsets, indicating that HCMV-specific effector CD8(+) T cells are actively induced by HCMV replication in healthy HCMV carriers. Phenotypic analyses of CD8(+) T cells using this classification will enable the characterization of antigen-specific CD8(+) T cells.

CD28 Antigens↗
PubMed2004

CD4+ effector T cell distribution in vivo: TGF-beta 1/TGF-beta receptor II interaction during activation mediates accumulation in the target tissue by preferential proliferation.

CD4(+) effector T cells generated in mesenteric lymph nodes (mLN) leave into the blood. Although they enter many tissues, mLN effector T cells are later found preferentially in the gut,the drainage area of mLN. We show in the rat that this is not an intrinsic property of mLN T cells. Instead, within the mLN milieu T cells are instructed by cytokines such as transforming growth factor beta 1 (TGF-beta 1) to up-regulate TGF-beta receptor II (TGF-beta RII) during activation. This enables effector T cells to continue proliferation upon subsequent contact with TGF-beta 1 in mLN and gut, and to accumulate in the lymph node draining area, the most likely site of pathogen invasion.

Animals↗
PubMed2005

The role of Fas ligand as an effector molecule in corneal graft rejection.

Previous studies have shown that the expression of Fas ligand (FasL; CD95L) by donor corneas is critical to their survival when placed on allogeneic recipients. Since there have been reports that the cornea expresses Fas, we tested the idea that FasL on lymphoid cells could be an effector molecule during rejection episodes. When FasL defective BALB/c-gld mice were engrafted with allogeneic corneas, significantly more of these corneas were accepted than by normal BALB/c mice. However, this was not due to impaired FasL-mediated effector function in these mice as the allogeneic corneas did not express detectable Fas by Western blot or RT-PCR analysis. Furthermore, donor corneas without Fas were given no survival advantage, but were rejected similar to wild-type donor allogeneic corneas. Examination of the T cell compartment in gld mice revealed that these cells express higher levels of Fas and are more susceptible to Fas-mediated death than wild-type cells. These results indicate that FasL is not an effector molecule in corneal graft rejection and that gld mice show reduced graft rejection due to greater susceptibility of their T cells to Fas-mediated apoptosis.

Animals↗
PubMed2005

Identification of effector-memory CMV-specific T lymphocytes that kill CMV-infected target cells in an HLA-E-restricted fashion.

HLA-E-restricted T cells represent a minor cytolytic T lymphocyte (CTL) population characterized by the surface expression of HLA class I-specific inhibitory receptors and by the capability of killing a large panel of allogeneic target cells (therefore named NK-CTL). Here we show that this subset of T cells is present in a sizeable fraction in the peripheral blood of human cytomegalovirus (HCMV)-seropositive healthy individuals. We provide evidence that NK-CTL recognize in an HLA-E-restricted fashion a naturally processed CMV-derived peptide in the transporter associated with antigen processing (TAP)-2(-/-) UL40+ RMA-S cell transfectants. Moreover, we show that they recognize and kill HCMV-infected target cells. NK-CTL are characterized by the CD8beta(dull) (CD45RA+)(CD28-)(CD27-)(CCR7-)(CD56+) surface phenotype, thus suggesting that they belong to the effector-memory cell compartment. Consistent with the effector-memory phenotype, they promptly produce IFN-gamma, but not IL-2, upon interaction with the specific HCMV UL40-derived peptide. Our data suggest that HLA-E-restricted CTL may represent an additional effector cell type involved in defenses against HCMV, a virus which escapes the control exerted by conventional CTL or NK cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Temporal cross-talk between TCR and STAT signals for CD8 T cell effector differentiation.

The strength and duration of signaling through surface receptors is a primary means of controlling cell fate decisions. In adaptive immunity, Ag-initiated T cell stimulation is secondarily regulated by cytokines. We here summarize evidence for temporal control of a gene expression program in naive CD8 T cells. It is initiated in response to TCR engagement but relies on secondary signaling from cytokine receptors to be sustained and to allow development of full effector capacity. This mechanism permits cytokine receptor signaling to rescue abortive TCR signaling, such as that induced in response to weak or partial TCR agonists. Indeed, limiting TCR-initiated signaling on the Ras/ERK pathway may be complemented by STAT activation. Thus, TCR- and cytokine-driven activation of transcription factors and epigenetic modifications may act in concert in a temporally staggered process to establish the functional program of effector CD8 T cells. Based on gene expression profiling, molecular targets whose activation or inactivation may boost or dampen CD8 T cell effectors are also identified. Manipulation of these targets may, respectively, increase anti-tumor responses or prevent graft-versus-host reactions.

Animals↗
PubMed2006

Enhanced cell survival of Hep3B cells by the hepatitis B x antigen effector, URG11, is associated with upregulation of beta-catenin.

Intrahepatic expression of hepatitis B x antigen (HBxAg) is associated with the development of hepatocellular carcinoma (HCC), perhaps through trans-activation of selected cellular genes. When this was examined by PowerBlot analysis, upregulated levels of beta-catenin and several known beta-catenin effectors were observed in HBxAg-positive compared with HBxAg-negative HepG2 cells. When HBxAg was introduced into Hep3B cells, upregulated expression of wild-type beta-catenin was observed. This was also observed in Hep3B cells overexpressing the HBxAg upregulated gene, URG11. Upregulated expression of URG11 and beta-catenin correlated with HBxAg trans-activation function. Transient transfection assays with fragments of the beta-catenin promoter showed that it was activated by both HBxAg and URG11 and inhibited by URG11-specific small inhibitory RNA. The latter also inhibited the growth of Hep3BX cells in a serum-free medium, which correlated with depressed levels of beta-catenin. Activation of beta-catenin effector genes was observed in cells stably expressing HBxAg or overexpressing URG11 compared with control cells transfected with the pTOPFLASH reporter plasmid. Extensive costaining between HBxAg, URG11, and beta-catenin was observed in infected liver and HCC nodules, suggesting a close relationship in vivo. In conclusion, wild-type beta-catenin is activated by HBxAg, in part, through the upregulated expression of the HBxAg effector URG11. URG11 stimulates the beta-catenin promoter and hepatocellular growth and survival. These observations also suggest that URG11 may be a regulatory element in the beta-catenin signaling pathway and may be a target for chemoprevention of HCC.

Adolescent↗
PubMed2005

Necrotic death but not irradiation abolishes costimulation of T-cell effector functions and survival by CD80-expressing tumor cells.

Tumor vaccination by the use of gene-modified cancer cells that provide costimulatory signals has been successfully applied in preclinical animal models and is currently evaluated in a variety of clinical settings. In previous work, we demonstrated the efficacy of B7.1/CD80 to promote tumor immunity in syngeneic murine models and to prevent deletion of activated T cells by activation-induced cell death (AICD). In clinical trials, tumor cell vaccines are generally inactivated to avoid transfer of live tumor cells, i.e., additional tumor burden. Previous data indicated, however, that inactivation of tumor cells by lethal ionizing irradiation abrogates tumor vaccination by CD80-expressing cells. Here, we compare living and irradiated allogeneic tumor cells regarding their capacity to induce T-cell effector functions and their propensity to interfere with T-cell deletion by apoptosis. Both lethally irradiated and nonirradiated tumor cells facilitated T-cell proliferation, tumor cell lysis, and interfered with T-cell AICD to a similar extent. In contrast, necrotic tumor cells failed to costimulate T-cell effector functions. Thus, irradiation does not seem to hamper tumor cell-mediated costimulation of T-cell effector functions. In contrast, necrosis of gene-modified tumor cells abrogates costimulation of T cells by CD80-expressing cells.

B7-1 Antigen↗
PubMed1980

Effector and enhancing lymphoid cells in plasmacytoma-bearing mice. II. Dynamic changes during tumor progression.

The Winn assay was used for the study of effector (tumor-inhibiting) and enhancing (tumor-promoting) lymphoid cells in BALB/c mice bearing MOPC-104E plasmacytomas. Kinetic studies with thymus, lymphnode, spleen and bone-marrow cells revealed that spleen, lymph node and to a lesser extent bone-marrow cells from 7- and 10-day tumor-bearers inhibited MOPC-104E growth, while at day 13 all three cell populations enhanced tumor growth. However, at day 16 strong tumor inhibition was observed again by spleen cells and to a lesser extent by lymph-node cells and thymocytes. Peritoneal cells from normal and tumor-bearing (7 and 10 days) animals enhanced tumor growth significantly. Separation of spleen cells on nylon wool columns showed that at 10 days the effector cells were T lymphocytes, but at a later stage (35 days) a different effector mechanism was present in the spleen. Treatment of MOPC-104E recipients with carrageenan or silica had little influence on tumor growth, but marked tumor inhibition occurred after lethal irradiation and bone-marrow reconstitution. This latter observation, together with the finding that bone-marrow, lymph node and peritoneal cells from normal donors enhanced tumor growth in several experiments, suggests that this plasmacytoma, like hormone-dependent tumors, requires lymphocyte-derived growth factors.

Animals↗
PubMed1982

DNA virus-transformed hamster cell--host effector cell interactions: level of resistance to cytolysis correlated with tumorigenicity.

Spontaneously cytolytic hamster spleen cells and BCG-activated hamster macrophages were used to examine susceptibilities to nonspecific effector cell-induced lysis among 13 DNA virus-transformed hamster cell lines exhibiting four different tumorigenic phenotypes. Hamster cells transformed by adenovirus type 12 (an oncogenic adenovirus serotype) or simian virus 40 (an oncogenic papovavirus) readily induced tumors in immunocompetent syngeneic hamsters and were relatively resistant to spleen-cell-induced lysis compared to cells transformed by adenovirus type 2 (a non-oncogenic adenovirus serotype) which induced tumors only in immunoincompetent hosts. Simian virus 40-transformed cells, which possess the unusual property of efficient tumor induction in allogeneic hosts, were uniquely resistant to lysis by activated macrophages. These differential patterns of susceptibility to cytolysis suggest an association between the level of transformed cell resistance to lysis by nonspecific host effector cells and the oncogenicity of the transforming virus. Furthermore, these data suggest that tumor-cell properties, other than those commonly associated with neoplastic transformation, determine the level of susceptibility or resistance to host effector cell mechanisms.

Adenoviridae↗