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PubMed1990

Protein kinase C-dependent up-regulation of CD5 surface expression on normal and lymphoblastoid T cells.

As an approach to study the mechanisms regulating the surface expression of CD5 antigen on T cells, the effects of agents that activate different lymphocyte functions were examined. Active tumour promoter agents (TPA), such as phorbol ester analogues [phorbol 12-myristate 13-acetate (PMA), phorbol 12, 13-dibutyrate (PBu2)] and mezerein, were able to increase the expression of CD5 on the cell surface of all T-cell lines), as deduced from immunofluorescence and immunoprecipitation analysis. The TPA-induced CD5 up-regulation occurred in a dose-and time-dependent manner and was dependent on protein and RNA synthesis. From the other stimuli tested, the T-cell mitogens [phytohaemagglutinin (PHA) and concanavalin A (Con A)], as well as monoclonal antibodies (mAb) against the CD3 complex, also increased CD5 expression, although to a lesser degree. In all cases the increments were shown to be dependent on protein kinase C (PKC), as evidenced by their inhibition with staurosporine, a potent inhibitor of PKC activation. These data suggest that CD5 up-regulation on T cells can be a physiological event that depends on PKC activation.

Antigens, Differentiation↗

PubMed1990

Human T cell receptor V alpha gene polymorphism.

The T cell receptor (TcR) is a heterodimer composed of an alpha,beta- or a gamma,delta-chain. The receptor is expressed on the cell surface in association with the CD3 complex, which in turn is composed of at least four chains (gamma, delta, epsilon, and zeta). In this review, we will summarize the recent findings on the genomic organization of the four T cell receptor genes, and the polymorphisms detected in the variable regions of these genes.

DNA Probes↗

PubMed1990

[Induction of cytotoxicity from human lymphocytes coated with bispecific antibody against human glioma cells].

A bifunctional hetero-F (ab') 2 fragment containing the Fab portions from anti-CD3 and anti-glioma monoclonal antibodies was prepared. The antibody simultaneously recognized two different molecules, the CD3 complex on effector T cells and human glioma-associated antigens on target glioma cells. This bispecific F (ab') 2 fragment induced peripheral blood lymphocytes (PBLs) from healthy donors to lyse cells of the human glioma cell line, U251MG, that is resistant to natural killer cell-mediated cytolysis. Compared with lymphokine-activated killer (LAK) activity which is obtained by exposure to interleukin (IL)-2 for more than 3 days, the maximum bispecific antibody-dependent cytotoxicity can be generated only after 24 hour exposure to IL-2. And cytotoxicity of lymphocytes triggered by the bispecific antibody was dependent upon the concentration of IL-2 in the culture medium. The effect of the bispecific antibody on LAK cells was tested in patients suffering from malignant glioma. One patient who received specific targeting therapy (LAK plus bispecific antibody) showed the disappearance of high density tumor mass from CT scan. But the patient who received only LAK therapy showed the recurrence of tumor one year after LAK treatment. These are preliminary data, but may be a promising approach in cancer immunotherapy.

Antibodies, Monoclonal↗

PubMed1989

The receptor with high affinity for IgE.

The cDNAs for each of the three types of polypeptide that form the high affinity IgE receptor have been cloned and sequenced. Analysis of the predicted amino acid sequence and other data suggests that the four-chained structure (alpha beta gamma 2) contains seven transmembrane segments. The alpha chain resembles the immunoglobulin-binding chain found in other Fc receptors, but the beta and gamma chain sequences do not resemble other known proteins. (The one exception: the transmembrane segment of the gamma chains, which is homologous to the corresponding segment of the zeta chain of the CD3 complex found on T lymphocytes). Efficient expression of IgE binding by the rat receptor in COS cells was observed only when the coding sequences for each of the three chains were co-transfected. So far, only the cDNA for the human alpha chain has been successfully cloned. We attempted to express this chain by co-transfecting its cDNA with those for the rat beta and gamma chains. Surprisingly, co-transfection with the cDNA for the gamma chain was sufficient, although when the beta and gamma chains were both co-transfected, expression of alpha beta gamma oligomers was evident. Approaches being used to define by genetic manipulation the functional role of various parts of the receptor are discussed.

Animals↗

PubMed1989

Prostaglandin E2-dependent induction of granulocyte-macrophage colony-stimulating factor secretion by cloned murine helper T cells.

PG are known to inhibit T cell proliferation, at least in part by suppressing IL-2 production, but effects of PG on the production of other lymphokines have not been well studied. We have found that PGE2 and PGE1, but not PGF2 alpha, inhibit both proliferation and production of granulocyte-macrophage (GM)-CSF by murine TH clones stimulated with Ag or anti-CD3 antibody. Thus, signals generated via the Ag receptor:CD3 complex were inhibited by PGE. Most interesting, however, was the finding that PGE2 and PGE1 could act synergistically with IL-2 for the induction of GM-CSF in some TH1 clones. Dependence on PGE2 for this response was not found in all clones, as some TH1 cells could produce GM-CSF after IL-2 alone, and some cells did not produce GM-CSF even in the presence of PGE2 and IL-2. These observations indicate that there is a subset of TH1 cells receptive to a stimulating activity of PGE2 in the presence of IL-2. PGE2 is known to elevate cAMP levels in T cells. Therefore, we tested whether other agents known to increase cAMP, such as forskolin and cholera toxin, could act in conjunction with IL-2 to induce GM-CSF secretion. As was found with PGE2, these compounds also induced GM-CSF activity in the presence of IL-2, suggesting a critical role for cAMP in this process. Overall these data indicate that the requirements for activation of GM-CSF secretion vary among individual T cells. Most importantly they provide the first evidence that E-series PG are positive signals for lymphokine induction in certain T cells, whereas simultaneously acting as negative signals limiting proliferation. This result also suggests that treatment with anti-inflammatory drugs that decrease PGE2 concentrations may inhibit lymphokine secretion normally stimulated by this pathway.

Alprostadil↗

PubMed1989

Phenotypic and functional analysis of gamma delta T cell receptor-positive murine dendritic epidermal clones.

Thy-1+ dendritic cells isolated from the epidermis of normal mice (dEC)3 bear the gamma delta TCR associated with the CD3 complex. We have analyzed the effects of antibodies directed against the TCR complex, Ly-6C, and Thy-1, as well as pharmacologic agents which have been shown to activate T cells without engagement of the TCR complex, on levels of intracellular free calcium, activation of protein kinase C, cytolysis, IL-2R expression, and secretion of lymphokines by dEC clones. We have found that the dEC cells express a fully functional TCR complex which can function to transmit signals upon perturbation leading to an increase in IL-2R expression, release of lymphokines, and cytolytic activity. These results indicate that the gamma delta TCR+ dEC are capable of responding to activation signals in the same manner as mature alpha beta TCR+ cells and suggests that they may play a functional role in the skin.

Animals↗

PubMed1989

T cell receptor-gamma and -delta genes preferentially utilized by adult thymocytes for the surface expression.

To assess the diversity of gamma delta receptors expressed on adult thymocytes we characterized the gamma- and delta-genes used in a panel of T cell hybridomas expressing a TCR-gamma delta-CD3 complex on the cell surface. DNA cloning and sequencing analysis were necessary to determine the used genes because of the presence of multiple rearrangements in these hybridomas. Among eight hybridomas analyzed, five used V gamma 4, two used V gamma 7, and one used V gamma 6 for gamma-genes, and four used V delta 5, two used V delta 4, and two used V delta 7 for delta-genes. The last delta-gene is documented for the first time. V gamma and V delta appear to pair randomly only restricted by the frequency of the utilization of individual V gamma and V delta segments. These gamma- and delta-genes contained N region addition between the V and J region in most cases. Both D delta 1 and D delta 2 regions were used in the most delta-genes as was seen previously. These results show that certain gamma- and delta-gene segments that are rarely used for the expression on fetal thymocytes are preferentially used by adult thymocytes. Also the repertoire of the gamma delta receptors on adult thymocytes is much greater than that on fetal thymocytes. BW5147 specific V4-C1 gamma-gene was expressed in all of the adult hybridomas. Inasmuch as this gene was not expressed in BW5147 cells or in fetal thymocyte hybridomas expressing V5 or V6 gamma genes, there exists a novel V gene segment-dependent control of transcription in the gamma-gene system.

Aging↗

PubMed1988

Phenotypic and functional characterization of human T cell clones.

The capacity of human peripheral blood-derived T cell clones to carry out a variety of functions was examined. T cell clones were generated by stimulating individual peripheral blood T cells with PHA by a procedure that yielded a growing clone from a mean of greater than 92% of the cultured cells. A total of 65 T cell clones (44 CD4+ and 21 CD8+) generated from two individual donors were examined for their functional capabilities. All T cell clones examined secreted IL-2, IFN-gamma, and lymphotoxin/tumor necrosis factor like activity when stimulated with immobilized mAb to the CD3 complex (64.1). When 54 additional T cell clones from a third donor were analyzed, all were found to produce IL-2. Upon activation with immobilized 64.1, all CD4+ clones and 91% of the CD8+ clones induced the generation of Ig-secreting cells from purified B cells. The CD8+ clones that did not serve as Th cells alone were able to augment the capacity of fresh CD4+ cells to generate Ig-secreting cells. Each of these clones was also found to effect MHC-unrestricted cytotoxicity upon activation with immobilized 64.1. The CD8+ clones were somewhat more effective killers than CD4+ clones, although there was considerable overlap. A total of 18 clones was analyzed for TCR beta-chain gene rearrangement. Of the clones exhibiting rearrangements of the beta-chain gene, 94% were found to have a single rearrangement pattern. Finally, the detailed phenotype of 15 (11 CD4+ and 4 CD8+) of these clones was examined. Variable numbers of cells of each of the clones expressed Ag identified by mAb 4B4 (CD29), Leu 8, Leu 15 (CD11b), and NKH1. Moreover, cells of 6 of 11 CD4+ clones and 4 of 4 CD8+ clones also expressed CD45R in addition to CD29; expression of CD45R and CD29 varied with the activation status of the clone. The current data demonstrate that nearly all of the T cell clones were able to accomplish each of the functions examined regardless of the surface phenotype. Inasmuch as the clones were generated using a technique that expanded more than 92% of the circulating T cells, the data imply that the progeny of the vast majority of T cells may have the inherent capacity to exert a wide array of functional activities.

Adult↗

PubMed1987

Proliferating cell nuclear antigen (PCNA)/cyclin in activated human T lymphocytes.

Proliferating cell nuclear antigen (PCNA), also called cyclin, is an intranuclear polypeptide whose synthesis reaches its maximum during the S-phase of the cell cycle. PCNA is expressed in several kinds of proliferating cells, one of which is the mitogen-stimulated human peripheral blood lymphocyte. PCNA expression increases from the late G1 phase through the S-phase of the cell cycle. This study is focused on the regulation of PCNA expression during the G1 phase of human T lymphocytes and on the relationship between PCNA expression and the rate of T cell proliferation. Special use is made of human autoantibodies to PCNA and the development of flow cytometry to label this intranuclear polypeptide. Unstimulated purified human peripheral blood T cells were PCNA negative. T cells treated with monoclonal antibody (64.1) to the CD3 complex expressed receptors for IL 2 but did not express PCNA until exogenous IL 2 was added to the culture. PCNA expression as well as the entry of the cells into S-phase could be inhibited by IL 2 receptor antibodies. Transferrin receptors were expressed only in T cells that were stimulated with both 64.1 and exogenous IL 2. Transferrin receptors were detectable before the cells expressed PCNA. Thus, the onset of PCNA expression is a phase in cell proliferation that follows transferrin receptor expression but preceded DNA synthesis. Drugs like dexamethasone and cyclosporin, which affect the early part of G1, inhibited PCNA expression; whereas cytarabine (ara-C) and hydroxyurea, which affect the S-phase and prevent DNA synthesis, did not block PCNA expression. There was a close correlation between the number of PCNA-positive cells and the number of S-phase cells in unperturbed T cell cultures. The highest level of PCNA expression was seen in cells that were in the first cycle after stimulation. The results show that PCNA expression is regulated by a signal after IL 2 binding and that PCNA labeling is a precise indicator for human T cells that are committed to DNA synthesis. Comparing these results with previous observations on the expression of some other activation-associated antigens, we suggest that the onset of PCNA expression represents a discrete step in T cell activation.

Antigens, Differentiation, T-Lymphocyte↗

PubMed1986

[T cell receptors. New knowledge of structure, genetic organisation, ontogenesis, and malignant transformation].

T cell receptors which are members of the "immunoglobulin-superfamily" are capable of discriminating "self" from "non-self" and can be considered as analogues membrane-bound immunoglobulins. The minimal essential component, an alpha/beta glycoprotein heterodimer, is structurally similar to Fab1-fragments of immunoglobulins with constant and variable domains. Its genomic organisation strongly resembles that of antibodies. The alpha/beta-heterodimer is found to be associated with the CD3 complex of T lymphocyte membranes triggering cell activation. Another member of the T cell receptor family, the gamma-chain, is expressed during early stages of intrathymic differentiations. Cytotoxic and helper T cell lines contain gamma-chain-specific mRNA in much smaller amounts. It may be a reliable marker of T cell malignancies. The T alpha-gene family is also involved in the pathogenesis of T cell malignancies.

Amino Acids↗

PubMed1986

Lymphoblastoid B cell lines produce an interleukin-1-like activity that can be serologically distinct from macrophage interleukin-1.

Antigen presentation by macrophages is accompanied by the production of interleukin-1 (IL-1) for successful T cell triggering. We have described EBV infected B cell lines that served as antigen presenting cells (APC) and now report the ability of these cells and their supernates, as well as EBV negative B cell lines, to support IL-2 production by a T cell line JM in the presence of the monoclonal antibody that recognizes the CD3 complex. Both EBV-transformed B cell lines and EBV-negative lines, and their supernates, exhibited IL-1-like activity in two different IL-1 dependent assays. These IL-1-like molecules were released constitutively from five of six EBV positive lines and three of five non-infected B cell lines. The activity from both, one virally infected and one non-infected B cell line, eluted from Sephadex G-75 in two peaks at 15-18K and 30-35K and could not be neutralized by antibody specific for macrophage IL-1. Supernates having IL-1-like molecules also contained a higher molecular weight inhibitor of proliferation. These data indicate that: both EBV-positive and EBV-negative B cell lines are capable of elaborating the IL-1-like activity; and the IL-1-like activity from these cells can be serologically distinct from macrophage IL-1. This suggests the presence of a family of molecules with IL-1 activity that derive from different cell types.

Animals↗

PubMed1988

A T cell receptor-associated GTP-binding protein triggers T cell receptor-mediated granule exocytosis in cytotoxic T lymphocytes.

To study the subcellular events occurring after T cell activation we used cloned human CTL permeabilized with alpha-toxin of Staphylococcus aureus. This method of permeabilization leads to stable transmembrane channels that permit the introduction of small molecules into the cell but preserves the cellular structures and macromolecular contents of the CTL. We used the exocytosis of CTL-specific serine esterases as a marker of T cell activation. The TCR-activated exocytosis is functioning in such permeabilized CTL. Introduction of the membrane impermeable guanosine nucleotide-binding protein (G-protein) activating GTP-analog GTP gamma S into CTL triggers exocytosis if Ca2+ is present. For optimal exocytosis ATP is required. The G-protein inactivating GDP-analog GDP beta S inhibited exocytosis triggered via the TCR-CD3 complex but not that triggered by activating the protein kinase C. If the protein kinase C was depleted in CTL by overnight incubation with phorbolester, the response to GTP-gamma S was reduced by more than 50%. These experiments demonstrate the presence of a G-protein involved in TCR-mediated CTL triggering. In the sequence of signaling steps this G-protein is localized after TCR-triggering but before the formation of the protein kinase C-activating phosphoinositol breakdown product diacylglycerol in the sequence of signaling steps.

Bacterial Toxins↗

PubMed1988

Signal transduction of gamma/delta T cell antigen receptor with a novel mitogenic anti-delta antibody.

Human T lymphocytes express either alpha/beta- or gamma/delta-TCR in association with the CD3 complex. We have isolated a mAb, delta TCS1, that immunoprecipitated the gamma/delta-TCR heterodimer from cell lysates of Peer and Molt-13 leukemia cell lines. After dissociation of the gamma- and delta-chains of TCR by treatment with SDS, delta TCS1 specifically immunoprecipitated the delta-chain. This antibody bound to the surface of other gamma/delta-positive T cell lines and clones and was able to stimulate the proliferation of a minor cell population (0.9 to 4.0%) of resting human PBL. Upon binding to gamma/delta-TCR-bearing Molt-13 cells and PBL, delta TCS1 elicited a fura-2 Caa+ signal indicating that the gamma/delta-receptor is functionally similar to the alpha/beta-heterodimer. These data indicate that the delta TCS1 antibody recognizes an epitope on TCR delta-chain and its mitogenic activity should be useful in characterizing the functional properties of human gamma/delta-positive T lymphocytes.

Animals↗

PubMed1994

CD59 costimulation of T cell activation. CD58 dependence and requirement for glycosylation.

In addition to the TCR-CD3 complex, T lymphocytes can be activated via another surface glycoprotein, the CD2 molecule. CD58 is the principal ligand for human CD2; CD59 and CD48 are two additional, low affinity ligands that have been defined for CD2. In this study, we have explored the role of CD59 in T cell activation. We have expressed human rCD58 and rCD59 molecules in Chinese hamster oocytes (CHO), and tested paraformaldehyde-treated transfectants for the ability to promote proliferation of and IL-2 secretion from PBMC and human purified T cells. We have shown that CD59 enhanced CD58-dependent T cell proliferation and IL-2 secretion in the presence of suboptimal concentration of PHA or a submitogenic combination of stimulatory anti-CD2 mAbs, presence of suboptimal concentration of PHA or a submitogenic combination of stimulatory anti-CD2 mAbs, T11-2 + T11-3. CD59-dependent costimulation was dependent on several factors including the level of co-expression of CD58, the ratio of CHO cell transfectants to T cells added in culture, the concentration of mitogen, and also donor-dependent differences. As expected, CD59 costimulation of CD58-dependent T cell proliferation was inhibited by Abs directed against CD59, CD58, and CD2. In our hands, the CD59 molecule itself, in the absence of CD58, was unable to support proliferation alone even in the presence of exogenous recombinant IL-1, IL-2, or IL-6. Finally, the ability of CD59 to enhance CD58-dependent T cell responses was shown to be dependent on N-glycosylation of CD59 at amino acid Asn18.

Animals↗

PubMed1995

Structure and diversity of the T cell antigen receptor beta-chain in a teleost fish.

Cell-mediated immunity (e.g., allograft rejection) is found in all vertebrates, and these reactions are known to depend on thymus-derived cells in amphibian, avian, and mammalian species. The participation of peripheral T cell-like lymphocytes subpopulations to fish immunity is now well documented, but the developmental origin, migration, and peripheral tissue distribution of these cells remain practically unknown. This is mainly due to the difficulty of efficiently thymectomizing fish at an early stage of development and to the lack of Ab strictly specific for thymocytes and T cell surface Ag. One strategy for analyzing T cell biology in fish would be to characterize the genes encoding polypeptides homologous to the TCR molecules. This report describes cDNA clones from the rainbow trout (Oncorhynchus mykiss) that have sequences very similar to amphibian, avian, and mammalian TCR beta-chains. Three complete trout V beta segments belonging to different families were analyzed; one of them had limited amino acid sequence similarity to the human V beta 20 family. The 10 trout beta-chain-joining segments all retain the invariant mammalian J beta residues, and comparison of 66 V beta-J beta junctions led to the identification of a D beta-like sequence (GGACAGGG) that is shorter than but very similar to the chicken D beta and mammalian D beta 1 sequences. There is considerable diversity at the V beta-D beta and D beta-J beta junctions, suggesting the presence of N-nucleotides. The trout C beta extracellular domain is shorter than mammalian C beta, and the hinge region has no cysteine residue. The transmembrane C beta domain contains a lysine residue that in mammals is thought to be involved in charged interactions with members of the CD3 complex.

Amino Acid Sequence↗

PubMed1995

[Immunocytochemical phenotyping of centroblastic lymphoma cells].

Using immunocytochemical phenotyping, the authors assessed the origin of malignant cells in a patient with malignant centroblastic lymphoma. The lymphoma cells expressed the thymocytic surface molecule CD1, pan T-lymphocytic markers CD2, CD5, CD6, CD7 with concurrent absence of complex CD3 and receptors for antigen on T lymphocytes. The proliferating activity of malignant cells could not be controlled by intensive cytostatic therapy.

Adolescent↗

PubMed1995

Efficient maturation of alpha beta lineage thymocytes to the CD4+CD8+ stage in the absence of TCR-beta rearrangement.

We have produced transgenic mice that express rearranged T cell Ag receptor gamma and delta transgenes in the alpha beta lineage of thymocytes. Thymi in these mice contain normal numbers of CD4+CD8+ cells that express low levels of the TCR-gamma delta. Analysis of the delta locus in these thymi indicates that these cells are in the alpha beta lineage even though they express the TCR-gamma delta. This shows that expression of the TCR-gamma delta in early thymocytes can lead to all of the consequences that are normally mediated by the beta-chain. These consequences include maturation to the CD4+CD8+ stage, entry into the cell cycle, and cessation of beta rearrangement. Therefore, the data support a model in which formation of a functional CD3 complex on immature CD4-CD8- thymocytes leads to further development in the absence of extracellular ligand recognition. The data also show that the gamma delta vs alpha beta lineage decision is made in a manner that is independent of gamma and beta gene expression.

Animals↗

PubMed1995

delta 9-Tetrahydrocannabinol modulates antigen processing by macrophages.

delta 9-Tetrahydrocannabinol (THC) exposure suppresses multiple immunological functions of macrophages. The ability of macrophages exposed to THC to process and present soluble protein antigens was investigated by the stimulation of antigen-specific helper T cell hybridomas to secrete interleukin-2. The T cell response to hen egg lysozyme was dramatically reduced after a 24-hr pretreatment of a macrophage hybridoma with THC. In contrast, THC exposure did not alter the capacity of the macrophage hybridoma to process chicken ovalbumin and augmented their presenting cell function for a pigeon cytochrome c response. These findings could not be attributed to differential effects of THC on either cell viability or expression of the antigen receptor-associated CD3 complex by the T cells. The level of T cell activation with peptides of lysozyme and cytochrome c, which do not require processing, was inhibited only at the highest concentrations of THC, suggesting that THC mainly affects antigen processing. Peritoneal macrophages exposed to THC during an antigen pulse and fixed with paraformaldehyde showed similar effects on the subsequent T cell responses to lysozyme and cytochrome c in the absence of THC, arguing against a possible influence of THC on the T cells. Therefore, THC differentially modulates the capacity of macrophages to process antigens that is necessary for the activation of CD4+ T cells.

Animals↗