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PubMed1980

Metabolic and cytoskeletal modulation of transferrin receptor mobility in mitogen-activated human lymphocytes.

The transferrin receptors which appear on mitogen-activated human peripheral blood lymphocytes were found by the use of immunofluorescence techniques to display temperature-dependent patching and capping reactions upon binding of transferrin. Lateral mobility of ligand-occupied membrane sites was accompanied by both shedding and endocytosis of receptor-transferrin complexes. In the presence of sodium azide or the microfilament inhibitor cytochalasin B, cap formation and shedding were markedly inhibited. In contrast, endocytosis of patched receptor-ligand complexes was inhibited by azide and microtubule inhibitors, including colchicine, vinblastine and vincristine. Co-capping experiments performed to elucidate further the alterations in membrane configuration involved in these reactions failed to reveal any topographical relationship between transferrin receptors and lectin-binding sites in these cells. These studied indicate that temperature-dependent mobility of transferrin receptors upon mitogen-activated peripheral blood lymphocytes is dependent upon the integrity of the cytoskeletal system and metabolic function of the cell.

Binding Sites↗
PubMed1978

Leukemic reticuloendotheliosis: polyclonal surface immunoglobulin on "hairy" cells.

The cytochemistry, surface markers and functional properties of purified mononuclear cells obtained from the peripheral blood and spleen of a patient with leukemic reticuloendotheliosis were studied. Nonspecific esterase activity, a monocyte marker, was demonstrable in 83% of the peripheral blood mononuclear cells and 84% of the splenic mononuclear cells. Rosetting techniques failed to detect T or B lymphocyte surface markers on the majority of the cells. Direct immunofluorescence revealed capped, noncytophilic surface immunoglobulin on the cells with all immunoglobulin classes being detectable. Since noncapping conditions ahd been used during immunofluorescence staining, the observed caps were attributed to in vivo binding of autoantibodies to the "hairy" cells. This conclusion was supported by the demonstration of susceptibility of the "hairy" cells to lysis mediated by normal allogeneic lymphocytes. It is postulated that the "hairy" cells in this patient are leukemic monocytes which bear autoantibodies directed against leukemia associated antigens.

Antibodies, Neoplasm↗
PubMed1992

Fc receptor expression, concanavalin A capping, and enzyme content of bovine neonatal neutrophils: a comparative study with adult cattle.

The increased susceptibility of newborns to infection may in part be related to impaired in vitro functions of neonatal polymorphonuclear neutrophils (PMNs). To evaluate early steps in the activation cycle of bovine PMNs we determined the expression of Fc receptors (FcRs) with an erythrocyte rosetting assay utilizing bovine anti-sheep immunoglobulin G2 IgG2 and the accumulation of ligand receptor complexes or "caps" with fluorochrome-coupled concanavalin A (Con A caps) on neutrophils from adult (A-PMN) and newborn (N-PMN) bovines. In addition, the levels of myeloperoxidase (MPO) and alkaline phosphatase (AP) were determined. FcR expression is reduced in N-PMNs (P less than .001), in contrast to results observed with human N-PMNs. Basal capping of Con A binding sites is reduced (P less than .05) in N-PMNs but is enhanced (P less than .001) upon pretreatment with colchicine (0.5, 5.0, and 50.0 microns). These findings are again contrary to results observed with human N-PMNs. Consistent with findings in human neonates, however, are reduced levels of cellular MPO (P less than .05) and elevated cellular AP (P less than .001) in the neonate. The functional significance of elevated AP levels and altered Con A capping in N-PMNs is unclear. However, diminished expression of FcR could potentially contribute to impaired adherence and phagocytosis of bacteria, and reduced activity of neutrophil MPO could indicate weaker microbicidal capacity of neonatal cells. The demonstrated impairment of N-PMN functions could potentially contribute to reducing the effectiveness of the cellular host defense system in neonatal calves.

Alkaline Phosphatase↗
PubMed1997

Involvement of p21racA, phosphoinositide 3-kinase, and vacuolar ATPase in phagocytosis of bacteria and erythrocytes by Entamoeba histolytica: suggestive evidence for coincidental evolution of amebic invasiveness.

Trophozoites of Entamoeba histolytica, the protozoan parasite that causes amebic dysentery, phagocytose bacteria in the colonic lumen and erythrocytes (RBC) in host tissues. Because tissue invasion is an evolutionary dead end, it is likely that amebic pathogenicity is coincidentally selected, i.e., the same methods used to kill bacteria in the colonic lumen are used by parasites to damage host cells and cause disease. In support of this idea, the amebic lectin and pore-forming peptide are involved in binding and killing, respectively, bacteria and host epithelial cells. Here amebic phagocytosis of bacteria, RBC, and mucin-coated beads was disrupted by overexpression of E. histolytica p21(racA-V12), a ras-family protein involved in selection of sites of actin polymerization, which had been mutated to eliminate its GTPase activity. p21(racA-V12) transformants were also defective in capping and cytokinesis, while pinocytosis of fluorescent dextrans was not affected. Wortmannin, a fungal inhibitor of phosphoinositide 3-kinase, markedly inhibited phagocytosis of bacteria, RBC, and mucin-coated beads by wild-type amebae. In contrast to p21(racA-V12) overexpression, wortmannin abolished amebic pinocytosis of dextrans but had no inhibitory effects on capping. Inhibition of amebic vacuolar acidification by bafilomycin also decreased bacterial and RBC uptake. These results, which demonstrate similarities between mechanisms of phagocytosis of bacteria and RBC by amebae and macrophages, support the idea of coincidental selection of amebic genes encoding proteins that mediate destruction of host cells.

Ammonium Chloride↗
PubMed1992

Major immunoglobulin capping deficiency in the peripheral blood B cells of patients with Sjögren's syndrome.

The capping of surface immunoglobulins (sIg) is a major characteristic of normal B lymphocytes. Thus, we have investigated sIg capping by peripheral blood (PB) B cells of patients with Sjögren's syndrome (SS) and we have found a major deficiency in these patients. In 12 healthy donors (HD), 8 +/- 2.8% of PB mononuclear cells were B cells (i.e. expressing the B-cell antigens CD19, CD20 and CD21 simultaneously) and more than 90% of these PB B cells were able to cap their sIg. In 12 experiments performed using PB lymphocytes from seven patients with SS, a major capping deficiency was noted with only 30% of PB B lymphocytes being able to cap sIg. This defect was not related to an expansion of the B-cell subpopulation expressing the CD5 antigen and was not observed in five patients with rheumatoid arthritis lacking SS. Capping of sIg via antigen binding (i.e. antigenic modulation) constitutes the initial signal for B-cell activation. This process is involved in anti-viral defence and could have a potential pathogenetic role in autoimmune diseases. This impaired B-cell function presently described represents an immune defect which could be important in the pathogenesis of SS.

Aged↗
PubMed1978

Altered membrane-associated functions in chronic lymphocytic leukemia cells.

Peripheral blood lymphocytes consisting mainly of neoplastic B cells from patients with chronic lymphocytic leukemia (CLL cells) showed a markedly reduced response to the human B-cell mitogens anti-beta2 microglobulin, Sepharose-bound protein A and Sepharose-bound anti-human immunoglobulin (anti F(ab')2) in all of nine patients studied. On the other hand, CLL cells from three out of eight patients tested responded well to the calcium ionophore A23187. Sepharose-bound protein A and anti-beta2 microglobulin also failed to induce increased uptake of 86Rubidium (potassium analogue) in CLL cells as compared to B-cell-enriched preparations of normal peripheral blood lymphocytes. The capacity of CLL cells to cap various surface markers including beta2 microglobulin was reduced. On the other hand, surface concentrations of beta2 microglobulin were not reduced as measured by fluorescein-labelled anti-beta2-microglobulin in single-cell cytofluorometry. It is concluded that various membrane-associated events elicited by ligand-receptor interactions are altered or blocked in CLL cells.

Aged↗
PubMed2000

Redistribution of selectin counter-ligands induced by cytokines.

Soluble recombinant (r) P-selectin and rP-selectin immobilized on plastic surfaces were tested for their capacity to activate neutrophils to produce superoxide anion. Soluble rP-selectin was incapable of activating leukocytes, whereas immobilized rP-selectin was able to induce leukocyte activation. When neutrophils were pretreated with a low dose of IL-8, granulocyte colony stimulating factor or granulocyte macrophage colony stimulating factor, soluble rP-selectin was no longer inert. These cytokine-primed leukocytes produced superoxide anion in the presence of soluble rP-selectin. During this priming period, sialyl Lewis X (sLe(X)) epitopes redistributed to one end of the leukocytes. Similar polarization of sLe(X) epitopes was observed at the attachment site of cells that adhered to immobilized rP-selectin. Cap formation and superoxide anion production induced by solid-phase P-selectin or by IL-8 and soluble rP-selectin treatment were inhibited by treatment of the leukocytes with cytochalasin B. These observations suggest that the redistribution of the carbohydrate ligands and the polarization of the leukocyte surface through an active process is a prerequisite but not sufficient to leukocyte superoxide production through P-selectin.

Cytokines↗
PubMed1984

Cross-linking surface immunoglobulin increases the stiffness of lymphocytes.

Cross-linking surface immunoglobulin (sIg) on B-lymphocytes causes a substantial increase in the mechanical stiffness of the cells. This has been demonstrated using a new method for measuring cellular deformability. The method is based on a device, the "Cell Poker", which we use to determine the force required slightly to indent or compress a cell adherent to a rigid substrate in culture. Cross-linking of sIg by bivalent anti-sIg antibodies is necessary to elicit the increase in stiffness; binding of monovalent Fab fragments is insufficient. The increase in stiffness is partially reversed by cytochalasin D and by completion of the capping of the cross-linked sIg. The modulation of cellular deformability and the induction of cellular dynamic processes such as capping are similar in their requirements for cross-linking sIg and in their sensitivity to cytochalasins. This suggests that both kinds of responses stem from similar cellular processes and structures. These results emphasize the mechanical capability of lymphocytes and suggest that the physiological functions of these cells are likely to employ this capability.

Animals↗
PubMed1988

Inhibition of cell movement and associated changes by hexachlorocyclohexanes due to unregulated intracellular calcium increases.

Hexachlorocyclohexanes (HCCHs) are potent stimulators of polymorphonuclear leukocyte (PMN) oxidative metabolism and of mobilization of calcium from intracellular stores. It was of interest, therefore, to evaluate the effect of HCCHs on PMN orientation and chemotaxis and to determine their effectiveness as chemotaxins. Chemotaxis was evaluated using micro-Boyden chambers, f-actin was quantitated by nitrobenzoxadiazole (NBD)-phallacidin fluorescence, and microtubules were quantitated by observing the concanavalin A (Con A) capping phenomenon. We also evaluated changes in intracellular calcium [Ca2+]i using quin 2 fluorescence. We found that the HCCH isomers were not chemotaxins and that the HCCH isomers that stimulated O2- formation (delta and gamma HCCH) inhibited chemotaxis. This effect was associated with inhibition of orientation. In addition, we found extensive inhibition of both f-actin and Con A cap formation. These effects of HCCH on cell function were associated with marked increases of [Ca2+]i. This work suggests that non-receptor-mediated increases of [Ca2+]i associated with HCCH have divergent effects on cell function and suggests that physiologic responses of PMNs requiring cytoskeletal alterations, such as chemotaxis, depend on the controlled responses of receptor-mediated stimulation.

Actins↗
PubMed1994

Leishmania major: association of the differentially expressed gene B protein and the surface lipophosphoglycan as revealed by membrane capping.

The lipophosphoglycan (LPG) of Leishmania promastigotes forms a dense glycocalyx which effectively covers the entire surface of the cell, and which undergoes structural modifications during the differentiation of promastigotes to the infective or metacyclic stage. Recently, the first protein marker for metacyclic promastigotes of Leishmania major has been characterized. This protein, termed gene B protein, is located on the cell surface, yet it lacks any hydrophobic sequence for membrane attachment. It does contain an unusual amino acid repeat that is related to the peptidoglycan binding domain of protein A from Staphylococcus aureus, suggesting that the protein might interact with metacyclic LPG via this domain for attachment to the cell. We have studied the distribution of LPG, gene B protein, and the major surface protease, gp63, by labeling them with immunogold or immunofluorescence prior to and during capping events. Thin sections of double-labeled parasites revealed that the gene B protein-gold particles were colocalized with the LPG-gold particles in the LPG capping structures at the extremities of the cell. Cocapping of LPG and gene B protein was also observed with two-color fluorescence. No similar redistribution was seen in gp63 or with integral membrane proteins. In contrast to the gene B protein, gp63 could only be immunogold labeled on the metacyclic surface after capping and shedding of the LPG, providing further that it and other membrane-associated proteins are normally buried under the LPG coat. The unusual surface exposure of the gene B protein is consistent with its hydrophilic and LPG binding properties, which allow it to become incorporated into the cell coat and to localize to the most external aspects of the cell.

Animals↗
PubMedDate not supplied

Defective mononuclear phagocyte function in systemic lupus erythematosus: relationship of FcRII (CD32) with intermediate cytoskeletal filaments.

To investigate the mechanisms of impaired Fc receptor-mediated mononuclear phagocyte system (MPS) clearance in systemic lupus erythematosus (SLE), we have examined FcRII (CD32) and vimentin function in 25 patients with SLE and 36 healthy adults. In SLE, FcR-mediated phagocytosis of IgG-sensitized bovine erythrocytes was decreased (5.9 +/- 2.47 vs. 8.3 +/- 3.59 erythrocytes phagocytosed/monocyte/h; p < 0.05), and CD32 and vimentin expression was within the normal range; however, the percentage of simultaneously CD32+ and vimentin+ cells was increased (30 +/- 12 vs. 20 +/- 13; p < 0.05). Circulating immune complexes (CIC) were positive in 11 SLE patients, and levels were positively correlated with proteinuria (r = 0.53; p < 0.05) and disease activity (r = 0.40; p < 0.05). The mobility of membrane molecules, measured as the percentage of patients that showed patching and/or capping of CD32, was increased compared with controls, but not significantly (p < 0.1). At the same time, redistribution of vimentin filaments was observed. In conclusion, our data seem to support the possibility of a functional and/or structural alteration in the relationship between Fc receptors and intermediate cytoskeletal filaments as a causative factor in the deficient internalization of ligands bound to Fc receptors in monocytes of SLE patients.

Adolescent↗
PubMed1979

IgG-binding sites on macrophage cell membrane. II. Mobility of Fc receptors induced by the interaction with their corresponding IgG ligands.

Mouse peritoneal macrophages were charged with IgG molecules in monomeric (mIgG), heat-aggregated (agIgG) or antigen-complexed (acIgG) form. Upon exposure to 37 degrees C, all bound IgG ligand types are redistributed on the cell surface due to the mobilization of their corresponding Fc receptor (FcR). The major findings regarding the fate of FcR on macrophages bearing IgG ligands are as follows: (a) the FcR involved in the binding of cytophilic molecules has a slow movement on the cell membrane and forms patches but never caps, while the opsonic type of FcR is rapidly capped; (b) the mobility of IgG-binding sites was temperature-dependent and was affected differently by sodium azide; this metabolic inhibitor enhances the disappearance of mIgG from the cell surface but decreases the capping and the disappearance of polymeric ligands; (c) both FcR types are probably ingested when complexed with specific ligand, and consequently, the rebinding of homologous IgG molecules is reduced, the clearing induced by agIgG or acIgG binding being much more extensive; and (d) cells cleared of their opsonic types of FcR are able to regenerate the receptor molecules with 8 h of incubation at 37 degrees C.

Animals↗
PubMed1984

Phorbol 12,13-dibutyrate enhances lateral redistribution of membrane glycoproteins in human blood lymphocytes.

Nanomolar concentrations of 4 beta-phorbol 12,13-dibutyrate markedly enhanced the redistribution of concanavalin A receptors, the common leukocyte antigen and the Lyt-3 antigen in human blood lymphocytes, as measured by cap formation. The effect on the lateral mobility of these cell surface molecules was dose dependent and occurred within a few minutes of treatment. 12-O-Tetradecanoyl phorbol 13-acetate, another tumor promoter, was similarly active. 4 alpha-Phorbol 12,13-didecanoate, which does not have tumor-promoting activity, did not enhance cap formation. The effect of various drugs and treatments indicated that the phorbol ester-enhanced cap formation was energy and temperature dependent and required functional microfilaments. Retinoic acid, an antitumor-promoting agent, was inhibitory and trifluoperazine, an inhibitor of calmodulin-dependent processes, had a minor inhibitory effect. Protein secretion and synthesis, extracellular Ca2+/Mg2+ and functional microtubules did not seem to be involved. The enhanced capping was inhibited by the alkylating agents tosyl phenylalanyl chloromethyl ketone and tosyl lysyl chloromethyl ketone but not by other protease inhibitors. The effect of various amino acid derivatives suggested the participation of an esterase. A comparative study of dose response, kinetics and sensitivity to drugs indicated a direct correlation between the phorbol 12,13-dibutyrate-enhanced redistribution of membrane glycoconjugates and the phorbol ester-induced binding (adhesion) between human blood lymphocytes, a phenomenon previously described.

Glycoproteins↗
PubMed1991

Wild type and tailless CD8 display similar interaction with microfilaments during capping.

We examined the influence of the intracytoplasmic region of CD8 alpha on capping and interaction with microfilaments. We used cell clones obtained by transfecting a CD4+ T-cell hybridoma with (a) T-cell receptor (TCR) alpha and beta chains from a cytolytic clone and (b) CD8 alpha genes that were either native or modified by extensive deletion of the intracytoplasmic region or replacement of the transmembrane and intracytoplasmic domains with those of a class I major histocompatibility complex gene (Letourneur et al. (1990). Proc. natn. Acad. Sci. U.S.A. 87, 2339-2343). Different cell surface structures were cross-linked with anti-T-cell receptor, anti-CD8 or anti-class I monoclonal antibodies and anti-immunoglobulin (Fab')2. Double labeling and quantitative image analysis were combined to monitor fluorescence anisotropy and correlation between different markers. Microfilaments displayed maximal polarization within two minutes. The correlation between these structures and surface markers was then maximal and started decreasing, whereas the redistribution of surface markers remained stable or continued. Furthermore, wild type and altered CD8 alpha exhibited similar ability to be capped and to induce co-capping of TCR and MHC (major histocompatibility complex) class I: the fraction of cell surface label redistributed into a localized cap ranged between 40% and 80%. Finally, cytochalasin D dramatically decreased CD8 capping in all tested clones. It is concluded that the transmembrane and/or intracellular domains of CD8 molecules are able to drive the extensive redistributions of membrane structures and cytoskeletal elements that are triggered by CD8 cross-linking.

Actin Cytoskeleton↗
PubMed1992

CD45 phosphotyrosine phosphatase and p56lck protein tyrosine kinase: a functional complex crucial in T cell signal transduction.

Tyrosine phosphorylation of several intracellular proteins is observed very early during T cell activation. p56lck, a non-receptor src-like protein tyrosine kinase (PTK) which is associated with the intracellular domains of CD4 and CD8 co-receptors, has been implicated in these early signal transduction events. Furthermore, recent experiments indicate that the receptor phosphotyrosine phosphatase, CD45, might be important in the regulation of p56lck PTK activity and that its expression is required for the generation of second messenger molecules following TCR triggering. Here, using co-capping experiments and double indirect immunofluorescence microscopy in functional human T lymphocytes, a specific co-distribution of a significant fraction of p56lck with CD45, but not with several other cell surface proteins, has been revealed. This is the first demonstration of a physical interaction between a receptor phosphotyrosine phosphatase and a PTK under physiologically relevant conditions. In addition, after antibody-induced capping of CD4, both a co-localization of p56lck and CD4, and concomitantly a significant increase in intracellular phosphotyrosine at the sites of CD4 caps were observed. In strong contrast to these results, co-clustering of CD4 with CD45 did not result in any detectable intracellular phosphotyrosine at the cap sites. These data indicate that CD45 can act on CD4-associated phosphoproteins in viable human T lymphocytes. Further, this provides evidence that p56lck PTK is a substrate of CD45 phosphotyrosine phosphatase in vivo and thereby supports the idea that CD45 is an early regulator of T cell activation involved in the modulation of the coupling of receptor-triggered events to intracellular signalling pathways.

CD4 Antigens↗
PubMed1984

Increasing extracellular potassium causes calcium-dependent shape change and facilitates concanavalin A capping in human neutrophils.

Stimulation of human polymorphonuclear leukocytes (PMN) by chemoattractants is associated with changes in membrane potential, and it has been speculated that these changes are important in PMN function. In the present study, human PMN isolated on Percoll gradients were exposed to extracellular K+ concentrations, which have been shown to depolarize PMN. Incubation of PMN at 37 degrees C for 15 min in 125 mM K+ increased the number that capped fluoresceinated concanavalin A (Con A) to 78% +/- 5.1 with 6.9% +/- 0.8 forming Con A caps in 5 mM K+ (p less than 0.001). In the absence of lectins, high K+ induced polarization of PMN shape with pseudopod and uropod formation (2.4% +/- 0.1 polarized in 5 mM K+ vs 83.4% +/- 1.0 polarized in 125 mM K+ p less than 0.001). Control studies, in which Na+ was decreased by substituting choline chloride or sucrose, indicated that the K+ effects were specific and not due to lowering of Na+. Increasing K+ also stimulated preferential secretion of the specific (secondary) granule constituents, caused significant mobilization of receptors for the peptide N-formyl-methionyl-leucyl-phenylalanine (fmet-leu-phe), and increased the number of PMN migrating in chemotactic assays. Unlike the capping of Con A and shape change, however, the increase in fmet-leu-phe binding, degranulation, and locomotion was not specific for raising extracellular K+ and occurred when choline chloride was substituted for sodium chloride, suggesting that these effects may be due to the lowering of Na+ or the changing of the Na+ to K+ ratio. In related studies designed to examine the mechanism of these K+-induced effects, shape change and Con A cap formation were inhibited by the absence of extracellular calcium or the presence of the calcium channel blockers, methoxyverapamil (100 microM), manganese (2 mM), or cobalt (2 mM), suggesting that the K+-induced changes depend on an influx of calcium. Thus, the increase of extracellular K+ induces calcium-dependent membrane changes in PMN similar to those seen when PMN are stimulated by a chemoattractant.

Adult↗
PubMed1982

Capping of cross-linked concanavalin A receptors on the surface of substrate-spread platelets.

Ligand-induced redistribution of concanavalin A (Con A) receptors on the surfaces of substrate-spread rabbit platelets was studied. These receptors were diffusely distributed on the surface of prefixed cells. Incubation of living cells with Con A and anti-Con A antiserum led to redistribution of corresponding receptors: These receptors were patched, removed from the upper surface of substrate-attached pseudopodia and lamellipodia, and accumulated on the surface of central cell parts. Capping of receptors was inhibited by cytochalasins B and D and by cold. Thus, capping of surface receptors can take place not only in large nucleated cells but also in platelets, that is, in small anucleate cell fragments. It is suggested that the cells of various types in the course of their attachment to the substratum form pseudopodia and lamellipodia that have a number of common characteristics, including the ability to move the cross-linked surface receptors centripetally.

Animals↗
PubMed1985

Lymphoma models for B-cell activation and tolerance. II. Growth inhibition by anti-mu of WEHI-231 and the selection and properties of resistant mutants.

Regulation of the growth of murine B-cell lymphomas has been used as a model for tolerance induction. The inhibition by anti-immunoglobulin reagents of the growth of WEHI-231 and several variant clones has now been studied. The parental line is exquisitely sensitive to growth inhibition by heterologous or monoclonal anti-mu or anti-k reagents and ceases to incorporate thymidine within 24-48 hr of exposure to anti-immunoglobulin reagents. Growth inhibition is initially reversible, but prolonged exposure to anti-mu results in cell death. This inhibition is specific for immunoglobulin light and heavy chains since growth is not inhibited by antibodies directed at either class I or class II histocompatibility antigens. In order to study the mechanism of growth inhibition, we have mutagenized WEHI-231 with ethylmethane sulfonate and cloned the surviving colonies in the presence of anti-mu. Such variants, which have been repeatedly recloned, are able to grow normally in the presence of anti-mu up to 100 micrograms/ml. These "resistant" clones, while expressing amounts of surface IgM similar to that observed on WEHI-231, do not differ markedly in their ability to cap their immunoglobulin receptors compared to the parental line but appear to have lost class II antigens. Cell cycle analysis revealed that anti-mu causes a block in the transition of WEHI-231 from G1 to S phase. The relevance of these processes to models of B-cell tolerance induction are discussed.

Animals↗