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PubMed1982

Cytochemical demonstration of increased adenosine triphosphatase activity in lymphocytes activated in vitro by phytohaemagglutinin or by the mixed lymphocyte reaction.

Cytochemical investigations of ATPase activity were performed on lymphocytes isolated from peripheral blood and activated in vitro by phytohaemagglutinin or by the two-way mixed lymphocyte reaction. Uncultured lymphocytes showed very little activity localized in small granules. The activity increased markedly during transformation. In fully transformed and actively proliferating cells, the ATPase activity was intense and localized in a crescentic perinuclear area of cytoplasm which was pale-staining and vesicular in Giemsa-stained preparations. In mitotic cells, the activity was in discrete granules or elongated structures suggestive of mitochondria, scattered throughout the cytoplasm. The ATPase activity had a pH optimum of 8.5 to 9.5 and was strongly inhibited at pH 7.5. The activity was stimulated by Ca2+ and Mg2+ and was inhibited by p-chloromercuribenzoate but not by oligomycin, which appeared to enhance the reaction. Lead nitrate at a concentration of 3 mM did not inhibit the reaction.

Adenosine Triphosphatases↗
PubMed1995

The murine BCL6 gene is induced in activated lymphocytes as an immediate early gene.

The chromosomal translocation involving 3q27 is often detected in human B-cell lymphomas, especially diffuse lymphomas with a large-cell component. The BCL6 gene has been isolated from the chromosomal breakpoint in these lymphomas. Here we cloned the murine BCL6 (mBCL6) cDNA from the muscle cDNA library using the human BCL6 (hBCL6) cDNA as a probe. The predicted amino acid sequence was 95% identical to that of hBCL6. It contains six repeats of the Krüppel-like zinc-finger motif that are completely identical to those of hBCL6, indicating that the BCL6 gene is well conserved between humans and mice. Expression of the mBCL6 gene was ubiquitously detected in adult mouse tissues including lymphatic organs. Furthermore, it was induced in lymphocytes activated with phorbol ester and Ca2+ ionophore within 30 min after stimulation. This induction was not inhibited by treatment of the cells with a protein synthesis inhibitor, cycloheximide. These results suggest that BCL6 plays a role in activated lymphocytes as an immediate early gene.

Amino Acid Sequence↗
PubMed1984

Deoxyadenosine (AdR) inhibition of newly activated lymphocytes: blockade at the G0-G1 interface.

The mechanism responsible for the lymphocytotoxicity associated with congenital adenosine deaminase (ADA) deficiency has been ascribed to an accumulation of dATP. Elevated levels of dATP can then lead to inhibition of DNA synthesis by inhibiting ribonucleotide reductase and causing a depletion of the other deoxynucleotide triphosphates (dNTP). This hypothesis was derived principally from studies with murine and human lymphoblastoid cell lines (LCL) and apparently confirmed in a limited number of investigations with lectin-stimulated lymphocytes. Our biochemical studies of lectin-stimulated mouse and human lymphocytes were not consistent with the dATP model and suggested that AdR exerted effects on lymphocyte activation that preceded the initiation of DNA synthesis. In the current studies, we focused on the effects of AdR on the early events in T lymphocyte activation, because we found they were the most sensitive to AdR toxicity. AdR blocked neither the production of T cell growth factor (TCGF) by lectin-stimulated lymphocytes nor the expression of TCGF receptors as detected by the anti-Tac monoclonal antibody that recognizes the human TCGF receptor. AdR did, however, block the early TCGF-dependent events leading to the entry into the cell cycle. By using the metachromatic fluorescence stain acridine orange, we found that AdR blocked the increased synthesis of RNA that characterizes the entry into the G1 phase of the cell cycle from the G0, resting state. Because these early effects were caused by the lowest doses of AdR, and because they preceded the synthesis of DNA by 15 to 20 hr, it suggested that these effects may be principally responsible for the in vivo toxicity associated with ADA deficiency. Furthermore, none of the other proposed biochemical mechanisms, e.g., inhibition of methylation, diminution of ATP levels, or incorporation of AdR into polyadenylated RNA, appeared adequate to explain AdR toxicity during T lymphocyte activation.

Animals↗
PubMed2001

Saquinavir up-regulates telomerase activity in lymphocytes activated with monoclonal antibodies against CD3/CD28.

The present study describes the effect of the HIV protease inhibitor saquinavir on telomerase activity and interferon-gamma (IFN-gamma) production of nonadherent mononuclear cells (NA-MNC). Cells obtained from peripheral blood of healthy donors were exposed in vitro to a mixture of monoclonal antibodies against CD3 and CD28 membrane antigens in order to activate prevalently T cell subsets. Treatment with saquinavir was performed at the time of cell stimulation. Thereafter, NA-MNC were tested for telomerase activity (TRAP assay) and interferon-gamma production up to 7 days later. The results show that saquinavir up-regulates telomerase activity and IFN-gamma release in activated NA-MNC. These observations suggest that the anti-HIV effects of saquinavir could be accompanied by other immunopharmacological properties, influencing some aspects of the functional activity of immunocompetent cells. These include possible antagonistic effects against lymphocyte senescence, through telomerase activation, and a potentiating activity on the production of IFN-gamma following T cell activation.

Antibodies, Monoclonal↗
PubMed1993

Antigen and helper T lymphocytes activate B lymphocytes by distinct signaling pathways.

Resting murine B lymphocytes can be induced to proliferate by cross-linking membrane immunoglobulin, the antigen receptor, or by contact with activated helper T lymphocytes in the absence of a signal through membrane immunoglobulin. Little is known about the molecular nature of contact-dependent T cell help. To determine whether helper T cells activate B cells through different signal transduction and second messenger pathways from those used by membrane immunoglobulin, the effects of drugs which block activation of B cells through membrane immunoglobulin were measured on B cell activation by contact with anti-CD3-activated and fixed T helper cells. Cyclosporin A, phorbol esters added at the time of activation, and cAMP agonists all block activation of B cells through membrane immunoglobulin at concentrations at least 100-fold lower than those necessary to block B cell activation by contact with activated Th1 or Th2 helper T cells. Depletion of protein kinase C by pretreatment of B cells with phorbol ester inhibits the proliferative response to anti-immunoglobulin but not the response to contact with activated T cells. The B cell response to lipopolysaccharide is intermediate in sensitivity to cyclosporin A and cAMP agonists, and resembles the response to activated T cells in resistance to phorbol esters and protein kinase C depletion. Various protein kinase inhibitors did not distinguish among these B cell activation pathways, except for the tyrosine kinase inhibitor, herbimycin A, which inhibited anti-immunoglobulin responses at 3- to 5-fold lower concentrations.

Animals↗
PubMed1977

Role of the tubulin-microtubule system in lymphocyte activation.

The role of the tubulin-microtubule system was examined in human peripheral blood leukocytes after activation with phytohemagglutinin (PHA). Soluble tubulin and microtubules were measured with a [(3)H]colchicine-binding assay. It was found that the tubulin content of PHA-activated lymphocytes was consistently increased relative to total protein content after 36 h of culture. There was no increase in the proportion of total tubulin synthesis which was present as microtubules at 36 h. Nevertheless, as a result of increased tubulin synthesis, there was a two-to three-fold increase in total microtubular mass. Colchicine, which disrupts microtubles, was used to assess the role of microtubule assembly in the sequence of events which follow lymphocyte activation, namely lymphokine release, protein synthesis, RNA synthesis, and DNA synthesis. Colchicine consistently inhibited DNA synthesis but did not inhibit release of the lymphokine, osteoclast activating factor (OAF). Protein and RNA syntheses were inhibited much less than DNA synthesis. The fact that some effects of PHA on lymphocytes appear to require intact microtubules and at least one does not suggest that the microtubule dependent step in PHA-stimulated lymphocyte activation occurs at a stage after propagation of the signal from the membrane to the cell interior.

Blood Proteins↗
PubMed1978

A chemical approach to the mechanism of B-lymphocyte activation. I. The pure presentation of haptens does not activate B lymphocytes.

In an attempt to definitively determine whether the pure presentation of haptens (on repetitive, non-metabolizable carriers) to B lymphocytes triggers differentiation to antibody-producing cells, dinitrophenyl and trinitrophenyl groups have been covalently coupled to potentially inert carriers (polymethylmethacrylate, chlorinated polyethylene and cellulose). The resulting conjugates (with three different degrees of hapten substitution) are not immunogenic. It is therefore concluded that the pure presentation of haptens to B lymphocytes does not trigger antibody formation.

Acrylic Resins↗
PubMed1976

Antibodies to guinea pig lymphokines. III. Reactions with radiolabeled lymphocyte activation products.

An antiserum raised against a purified fraction of guinea pig lymphokines exhibits marked in vivo properties; it suppresses delayed hypersensitivity reactions and binds migration inhibition factor (MIF) from supernatants of activated lymphocyte cultures in vitro. This serum was analyzed for specificity using a radioactive double labeling technique which distinguishes products synthesized either de novo or in increased amounts by stimulated lymphocytes. Combined supernatants of stimulated (concanavalin A or PPD) and unstimulated cultures labeled with either tritiated or [14C]leucine, respectively, were fractionated on Sephadex G-75. Pooled fractions were precipitated using the antibody sandwich technique, and solubilized precipitates were analyzed using sodium dodecyl sulfate polyacrylamide gel electrophoresis. Using this procedure the anti-lymphokine serum recognized primarily three newly sythesized lymphocyte activation products with molecular weights of approximately 60 000, 45 000 and 30 000 daltons. By contrast, these molecules could not be detected in radiolabeled lymph node cells which had been solubilized with NP-40 detergnt. The isoelectric point of all three molecules was found to be 5.2 +/- 0.3. The previously determined characteristics (mol.wt. 45 000, pI 5.2) of MIF and the property of the anti-lymphokine serum to absorb MIF activity suggest an identity between MIF and one of the molecules. In view of the previously described in vivo effects of the anti-lymphokine serum it is concluded that at least one of these three molecules plays an important role in the early events of delayed-type hypersensitive reactions in vivo.

Animals↗
PubMed1984

[Liver regeneration and the immune system. II. Suppressor activities of lymphocytes activated in vivo by liver regeneration and their genetic control].

The lymph node cells (LNC) activated in vivo by liver regeneration following partial hepatectomy of mice (pLNC: primed lymph node cells) respond to regenerating liver cells in vitro with typical secondary immune response characteristics (as shown in Paper I). These lymph node cells activated in vivo suppress the proliferation of responder lymphocytes cultured with mitomycin C (MMC)-treated regenerating syngeneic liver cells (sMLHLR). The suppressive activity was already present in LNC 4 days after partial hepatectomy and remained unchanged for at least 16 days. These pLNC were effective not only on sMLHLR but also on syngeneic mixed lymphocyte culture (sMLR) and allogeneic mixed lymphocyte culture (MLR), of which responder cells share I-A (I-B) subregions of MHC with pLNC. The pLNC restimulated in vitro with regenerating liver cells (ppLNC: in vitro reactivated pLNC) suppress the proliferation of syngeneic responder cells in sMLR, but not of cells from congeneic mice differing from the ppLNC at a cluster of genes linked to the Ig locus. Thus the suppressive activity of pLNC is controlled by the I-A (I-B) subregions of the MHC and that of ppLNC by genes in the Ig region.

Animals↗
PubMed1983

Regeneration and the immune system. II. Suppressor activities of lymphocytes activated in vivo by liver regeneration and their genetic control.

The lymph node cells (LNC) activated in vivo by liver regeneration following partial hepatectomy of mice (primed lymph node cells) respond to regenerating liver cells in vitro with typical secondary immune response characteristics (Miyahara, S. et al., Eur. J. Immunol. 1983. 13: 878). These LNC activated in vivo suppress the proliferation of responder lymphocytes cultured with mitomycin C-treated regenerating syngeneic liver cells (sMLHLR). The suppressive activity was already present in LNC 4 days after partial hepatectomy and remained unchanged for at least 16 days. These primed LNC were effective not only on sMLHLR but also on syngeneic mixed lymphocyte culture (sMLR) and allogeneic mixed lymphocyte culture, of which responder cells share the I-A (I-B) subregions of the major histocompatibility complex (MHC) with primed LNC. At least one cell in the suppressor circuit is a T cell. The primed LNC restimulates in vitro with regenerating liver cells (in vitro reactivated primed LNC) suppressed the proliferation of syngeneic responder cells in sMLR, but not of cells from congeneic mice differing from the in vitro reactivated primed LNC at a cluster of genes linked to the Ig locus. Thus the suppressive activity of primed LNC is controlled by the I-A (I-B) subregions of the MHC and that of in vitro reactivated primed LNC by genes in the Ig region. The role of these suppressive cells in liver regeneration is discussed.

Animals↗
PubMed2003

Augmentation effects of lymphocyte activation by antigen-presenting macrophages on FDG uptake.

OBJECTIVE: Research on FDG-uptake by blood cells has revealed that FDG is incorporated by macrophages and granulocytes, as well as activated lymphocytes. These characteristics of FDG suggest the possibility of visualizing the distribution of immunocytes in target organs. The aim of this study was to investigate if mouse spleen-derived lymphocytes, activated by macrophages presenting sheep red blood cell (sRBC) antigens, could be traced by FDG. METHODS: One percent of a sRBC suspension was injected into the peritoneal cavity of mice thereby creating immunity to the sRBC antigen. The splenocytes, consisting mostly of lymphocytes, were isolated, and serum containing the anti-sRBC antibody was mixed with sRBC to prepare sRBC-antibody complexes (sRBC-AbCs). Then five percent of a thioglycolate medium was injected into the peritoneal cavity of the same mice, and macrophages of ascitic cell origin were obtained. These macrophages were added to the sRBC-AbCs to induce sRBC antigen presenting macrophages. These were incubated with splenocytes obtained from sRBC immunized mouse (sRBC immunized splenocytes) or non-immunized splenocytes to induce a T cell immune response. [3H]deoxyglucose ([3H]DG) and FDG were incorporated in splenocytes, and the quantity of their uptake was measured. RESULTS: [3H]DG uptake by sRBC-immunized splenocytes was about eleven times as high as that of non-immunized splenocytes. In contrast, [3H]DG uptake by sRBC-immunized splenocytes, co-cultured with macrophages phagocytizing sRBC-AbCs, was about 40 times higher compared with non-immunized splenocytes. Splenocytes in non-immunized mice picked up very little [3H]DG, despite co-culture with macrophages phagocytizing sRBC-AbCs. Similar tendencies were observed with FDG. CONCLUSIONS: These results suggest that the SUV calculated in PET reflects not only the number of lymphocytes, but also the activation state of the lymphocytes themselves. In addition, the biodistribution of antigen specific lymphocytes, that have been taken up FDG in vitro and returned to the body, can be observed through PET.

Adult↗
PubMed1986

Mechanism whereby ouabain inhibits human T lymphocyte activation: effect on the interleukin 2 pathway.

Through the blockade of the Na-K-ATPase, ouabain inhibits several biochemical and biological events leading to the proliferation of activated lymphocytes. Since we already found that interleukin 1 production was not prevented by ouabain, we investigated by which mechanism this drug inhibits mitogen-induced human T lymphocyte activation, with respect to the interleukin 2 (IL 2) pathway. Our data revealed that at concentrations lower than 0.2 microM, IL 2 accumulation was not reduced in ouabain-treated cultures, even when cell proliferation was completely inhibited (0.1-0.2 microM ouabain). Moreover, in this concentration range, ouabain stimulated in a dose-dependent manner the accumulation of IL 2 in the supernatant of Con A-stimulated lymphocytes (optimum for 0.05 microM corresponding to half inhibition of lymphocyte proliferation). Such an effect, which appears correlated to the inhibition of Na-K-ATPase, suggests a failure of the cell to utilize IL 2. At concentrations higher than 0.3 microM, ouabain inhibited both lymphocyte proliferation and IL 2 production. These observations show that the glycosteroid interacts differently with the different cell populations involved in the cascade of reactions leading to cell proliferation, and suggest that the mitogenic inhibition resulting from the blockade of Na-K-ATPase is not related to the blockade of IL 2 production. On the other hand, we observed that: ouabain inhibited the expression of the receptors for IL 2, an obligatory step in lymphocyte proliferation; ouabain blocked the proliferation of an IL 2 sensitive human T cell line; in both cases the inhibition paralleled that of lymphocyte proliferation. Our data suggest that the essential steps of lymphocyte proliferation in which Na-K-ATPase-dependent K+ fluxes play a critical role are the expression of IL 2 receptors and the IL 2-dependent proliferative step.

Cell Line↗
PubMed1989

[Analysis of T-cell subpopulations and expression patterns of lymphocytic activation markers in patients in the early phase following kidney transplantation using laser flow cytometry].

In 10 patients after kidney transplantation the T cell subpopulations (CD4, CD8) and the number of activated lymphocytes (IL-2R and transferrin receptor+, 4F2+, HLA-DR+, CD3+) in the peripheral blood were determined. In 9 out of 9 cases with rejection a clear immune activation could observed. In patients with CMV-associated rejection crisis the CD4/CD8 ratio was significantly higher compared with patients with rejection crisis but without CMV infection. In all patients with CMV infection (n = 5) an increase of activated lymphocytes was observed. In a clinical-immunological monitoring the dynamics of the CD4/CD8 ratio, the expression of activation marker (especially CD3+, HLA-DR+ and 4F2+) and the absolute number of lymphocyte subpopulations should included.

Adult↗
PubMed2000

Inhibition of T lymphocyte activation in mice heterozygous for loss of the IMPDH II gene.

Inosine 5'-monophosphate dehydrogenase (IMPDH) is the rate-limiting enzyme in the de novo synthesis of guanine nucleotides, which are also synthesized from guanine by a salvage reaction catalyzed by the X chromosome-linked enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Since inhibitors of IMPDH are in clinical use as immunosuppressive agents, we have examined the consequences of knocking out the IMPDH type II enzyme by gene targeting in a mouse model. Loss of both alleles of the gene encoding this enzyme results in very early embryonic lethality despite the presence of IMPDH type I and HPRT activities. Lymphocytes from IMPDH II(+/-) heterozygous mice are normal with respect to subpopulation distribution and respond normally to a variety of mitogenic stimuli. However, mice with an IMPDH II(+/-), HPRT(-/o) genotype demonstrate significantly decreased lymphocyte responsiveness to stimulation with anti-CD3 and anti-CD28 antibodies and show a 30% mean reduction in GTP levels in lymphocytes activated by these antibodies. Furthermore, the cytolytic activity of their T cells against allogeneic target cells is significantly impaired. These results demonstrate that a moderate decrease in the ability of murine lymphocytes to synthesize guanine nucleotides during stimulation results in significant impairment in T-cell activation and function.

Animals↗
PubMed1998

Activated lymphocytes reduce adherence of Aspergillus fumigatus.

Lymphocytes comprise up to 30% of the cells present in human bronchoalveolar lavage fluid and thus could participate in host response to infectious Aspergillus fumigatus conidia. We have examined the possibility that lymphocytes might play a role during early infection by either damaging the fungus or interfering with adherence. When incubated with A. fumigatus conidia for 20 h, highly purified 5-day-old lymphocytes activated with either IL-2 or phytohaemagglutinin, but not untreated lymphocytes, were consistently able to reduce residual fungal biomass as estimated by a metabolic assay. T lymphocytes, but not NK cells, appeared to be responsible for this activity. Lymphocytes bound both A. fumigatus conidia and hyphae, and the antifungal activity of the lymphocytes required direct lymphocyte fungus contact. In a separate set of experiments using release of 51Cr from 51Cr-loaded fungi as an estimate of fungal damage, lymphocyte-induced loss of fungal biomass was found to be due to loss of fungal adherence rather than to direct fungal damage. The detached hyphae were also found to be metabolically intact and to have normal morphology by electron microscopy. These data demonstrate that IL-2- and phytohaemagglutinin-activated lymphocytes exhibit a contact-dependent ability to reduce adherence of germinating conidia of A. fumigatus to a surface.

Aspergillus fumigatus↗
PubMedDate not supplied

Reduced lymphocyte activation in repeatedly inflamed human tonsils.

Tonsils of 20 patients with recurrent tonsillitis were investigated. Activated lymphocytes, that is lymphocytes with increased nuclear birefringence, were found in only 3 cases. The lack of lymphocyte activation is supposedly due to reduced antigen stimulation. Since antigens arrive at the tonsillar lymphoid tissue via the follicle-associated cells of the crypt epithelium, the ultrastructure of this epithelium was also studied in 5 cases. Tonsils of three dogs were used for comparison. In the repeatedly inflamed human tonsils the follicle-associated, so-called M cells contained fewer intracytoplasmic tubules and vesicles than those of the dogs. Moreover the frequency of these cells seemed to be reduced. Most of the crypts of inflamed tonsils were lined with a non-reticulated, stratified squamous epithelium. A hypothesis is presented on the pathomechanism of recurrent tonsillitis and suggestions are put forward about its pathohistology.

Adolescent↗