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At least 469 records · Page 26Linked to original sources
PubMed1991

Evidence that the CD45 phosphatase regulates the activity of the phospholipase C in mouse T lymphocytes.

The importance of the tyrosine phosphatase CD45 in the regulation of lymphocyte activation was first demonstrated using antibodies against the extracellular domain of CD45 in functional assays. More recently it was reported that CD45-negative mutants were nonresponsive to stimulation through the T cell receptor-CD3 complex. We have studied the effect of CD45 cross-linking on the early signals induced by CD3 in mouse T cells. We show that CD45 cross-linking inhibits the increase in inositol phosphates and cytoplasmic Ca2+ induced by cross-linking of CD3. This indicates that CD45 is involved in the regulation of phospholipase C.

Animals↗
PubMed1991

CD4+CD8+CD3high thymocytes appear transiently during ontogeny: evidence from phenotypic and functional studies.

During T cell development thymocyte subsets emerge in a defined order, reflective of their maturational stage. In this study we determined the timing of appearance of CD4+CD8+CD3high thymocytes during in vivo and in vitro embryonic development, and thymic reconstitution after cortisone treatment. In these models, CD4+CD8+CD3high cells followed CD4+CD8+CD3low and preceded mature CD4+CD8-CD3high/CD4-CD8+CD3high thymocytes, while cortisone resistance was first seen among CD4+CD8+CD3high cells. CD4+CD8+CD3high thymocytes were also shown to display a pattern of antigen receptor-mediated calcium influx intermediate between that induced in other CD4+CD8+ cells and mature thymocytes. These results are consistent with a precursor-progeny relationship between CD4+CD8+CD3low and CD4+CD8+CD3high thymocytes, the latter developing to mature thymocytes (Hugo, P. et al., Int. Immunol. 1991. 3: 265).

Animals↗
PubMed1991

Cross-linking of surface IgM activates NF-kappa B in B lymphocyte.

In B lymphocytes, cross-linking of surface IgM activates changes in both the cell cycle and differentiation. In normal B cells and B cell tumors, many stimuli induce the activation of NF-kappa B and its translocation from the cytoplasm to the nucleus. In this study we sought to determine if cross-linking of surface IgM led to the activation of NF-kappa B. Our results show that activation of B cells by cross-linking anti-IgM antibodies activated NF-kappa B in the murine B lymphoid cell lines 70Z/3 and M12, and in the dense fraction of splenic cells. The activation of NF-kappa B required optimal doses of anti-IgM antibodies and took 5 to 10 min to reach maximal levels. Cross-linking of IgM has also been shown to activate protein kinases including protein kinase C (PKC). To test whether PKC activation was required for NF-kappa B translocation, we treated 70Z/3 cells for 18 h with phorbol 12-myristate 13-acetate, a procedure which depletes these cells of functional PKC. This treatment did not abrogate the nuclear translocation of NF-kappa B following anti-IgM cross-linking. These results indicate that the nuclear translocation of NF-kappa B is rapidly induced by surface IgM cross-linking and that this activation appears to use a pathway which does not require PKC.

Animals↗
PubMed1992

CD45 modulates T cell receptor/CD3-induced activation of human thymocytes via regulation of tyrosine phosphorylation.

Stimulation of thymocytes or mature T cells via the T cell receptor (TcR)/CD3 complex activates a cascade of processes inducing cells to enter the cell cycle. A key step is the activation of phosphatidylinositol-specific phospholipase C (PI-PLC) within seconds following TcR/CD3 stimulation, an event which is strongly enhanced by co-ligation of the CD4 (or CD8) accessory molecule with TcR/CD3. In contrast, co-ligation of CD45 inhibits the same TcR/CD3 responses. The machinery which couples the TcR/CD3 complex, CD4, and CD45 to PI-PLC appears to involve regulation of tyrosine phosphorylation, as the TcR/CD3 and CD4 receptors are associated with the tyrosine kinases p59fyn and p56lck, respectively, and CD45 has intrinsic tyrosine phosphatase activity. Here, we have examined the ability of CD45 to regulate signal transduction via TcR/CD3 in human thymocytes. Co-cross-linking CD45 to the TcR/CD3 complex strongly suppressed the tyrosine phosphorylation of several intracellular substrates normally seen following TcR/CD3 stimulation. This effect of CD45 was associated with inhibition of a rise in intracellular calcium following TcR/CD3 ligation. Since TcR/CD3 stimulation of mature T cells induces tyrosine phosphorylation of PLC gamma 1, we investigated this phenomenon in thymocytes, and asked whether ligation of CD45 might regulate this process. By immunoprecipitation we found that TcR/CD3 stimulation induced tyrosine phosphorylation of PLC gamma 1, an effect which was enhanced by co-cross-linking CD4 to TcR/CD3. In contrast, co-ligation of CD45 strongly blocked PLC gamma 1 phosphorylation induced by either stimulus. Consistent with previous findings in mature T cells, CD45 cross-linking was able to partially inhibit TcR/CD3-induced thymocyte proliferation when interleukin 2 was used as a second signal, but almost completely (80%-90%) blocked proliferation when anti-CD28 mAb was used as the second signal, suggesting that CD45 cross-linking may be able to block interleukin 2 production via the CD28 pathway. These effects of CD45 on TcR/CD3 signaling and proliferation in thymocytes point towards a potential role for this pathway in thymic selection.

Antigens, CD↗
PubMed1993

Distinct patterns of early response gene expression and proliferation in mouse mast cells stimulated by stem cell factor, interleukin-3, or IgE and antigen.

Stem cell factor (SCF) is encoded at the Sl locus of the mouse and is the ligand for the c-kit receptor. Recombinant rat SCF164 (rrSCF164) induces proliferation and promotes maturation of mouse mast cells in vitro and in vivo and can also induce c-kit receptor-dependent mouse mast cell degranulation. We now report that in both quiescent and non-quiescent mouse bone marrow-derived cultured mast cells (BMCMC) rrSCF164 induces increased mRNA levels for the "early response genes" c-fos, c-jun and junB but has only slight effects on the expression of junD. Recombinant mouse interleukin-3 (IL-3) also promotes proliferation of both quiescent and non-quiescent BMCMC. However, IL-3 induces increased expression of c-fos and junB only in quiescent BMCMC. Cross-linking of Fc epsilon receptor type I (Fc epsilon RI) on BMCMC by IgE and specific antigen induces a pattern of early gene expression very similar to that induced by rrSCF164. However, BMCMC stimulated through the Fc epsilon RI did not proliferate and, in comparison to control BMCMC, exhibited significantly decreased proliferation in response to rrSCF164 or IL-3. These results indicate that stimulation of BMCMC proliferation by IL-3 or rrSCF164 induces distinct patterns of early response gene expression and suggest that the proliferative effects of these growth factors may be mediated through distinct signal transduction pathways. Our data also point to previously unappreciated similarities between the effects of signaling through the c-kit receptor or the Fc epsilon RI on mast cell expression of fos and jun genes.

Animals↗
PubMed1994

Neuronal interferon-gamma immunoreactive molecule: bioactivities and purification.

An interferon (IFN)-gamma immunoreactive molecule, localized to small neurons in peripheral sensory ganglia (N-IFN-gamma), has been detected with two mouse monoclonal antibodies (DB1 and DB16) directed against different epitopes of rat IFN-gamma. To define N-IFN-gamma with regard to its protein characteristics and bioactivities, DB1 and DB16 were used to purify N-IFN-gamma from rat trigeminal ganglia in a two-step sequential antibody-affinity procedure. Sodium dodecylsulfate polyacrylamide gel electrophoresis (PAGE) and silver staining of purified N-IFN-gamma displayed three bands with an approximate molecular mass of 66, 62 and 54 kDa. The N-IFN-gamma bioactivity was confined to the protein stained on gel when native material was run on PAGE. Biological effects of pure N-IFN-gamma were examined and compared with those of lymphocyte-derived recombinant IFN-gamma. N-IFN-gamma had antiviral effects in vitro and induced major histocompatibility complex class I and II antigens on macrophages and in cells in skeletal muscle cell cultures. N-IFN-gamma also stimulated myoblast proliferation and affected cholinergic receptor distribution on myotubes similar to recombinant IFN-gamma. Both molecules potently stimulated Trypanosoma brucei brucei growth. These data suggest that, although N-IFN-gamma is a protein distinct from lymphocyte-derived IFN-gamma, the two molecules have enough structural similarities to allow for antibody recognition of at least two epitopes, and action on similar target structures on both parasite and mammalian cells.

Animals↗
PubMed1994

Cross-linking CD28 leads to activation of 70-kDa S6 kinase.

Proliferation of T lymphocytes in response to antigen/MHC complexes is dependent upon the presence of a co-stimulatory signal; in its absence, T cells are rendered unresponsive to specific antigen CD28 is a T cell surface glycoprotein that acts as a co-stimulatory molecule when combined with signals initiated by the T cell receptor CD3 complex. While the biochemical signaling events following CD28 stimulation are still poorly defined, monoclonal antibodies (mAb) directed against CD28 have been shown to transduce a variety of early signals that are different in the presence of cross-linking antibody or the presence of phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC). Stimulation of human T cells with cross-linked anti-CD28 mAb alone resulted in the activation of 70-kDa (p70) S6 kinase, a rapamycin-sensitive serine/threonine kinase that is believed to be important for cell cycle progression. Activation of p70 S6 kinase through CD28 was inhibited by rapamycin. Activation of p70 S6 kinase also increased in response to cross-linked CD3, but followed a more rapid time course than activation via CD2. Cyclosporin A and FK506 had no effect on p70 S6 kinase activity initiated via either pathway. The combination of cross-linked CD28 and cross-linked CD3 had no more than an additive effect on the induction of p70 S6 kinase activity. Thus, recruitment of p70 S6 kinase activity appears to represent a common signal transduction event shared by both the CD28 and CD3 pathways of T cell activation.

CD28 Antigens↗
PubMed1994

Co-stimulation with LFA-1 triggers apoptosis in gamma delta T cells on T cell receptor engagement.

Stimulation of T cells through the T cell receptor (TcR) initiate activation pathways, and paradoxically can also result in activation-induced cell death. Many factors influence a stimulated cell's decision to manifest one or the other. Here we show that co-stimulation with LFA-1 plays a key role in the choice between the two fates, differentiating between alpha beta and gamma delta T cells. Peripheral gamma delta. T cells but not alpha beta T cells undergo apoptosis upon co-cross-linking of TcR and LFA-1 in MRL lpr/lpr mice as well as +/+ mice. Our results suggest that apoptosis of gamma delta T cells is inducible by combined stimuli independent of the Fas-mediated pathway.

Animals↗
PubMed1995

Co-ligation of mouse complement receptors 1 and 2 with surface IgM rescues splenic B cells and WEHI-231 cells from anti-surface IgM-induced apoptosis.

Recent studies have shown that complement receptors play important roles in both T-dependent and T-independent B lymphocyte responses to low doses of antigen (Ag) in vivo. Complement activation by either the classical or alternative pathway results in the covalent binding of C3 molecules to Ag in forms that ligate complement receptors type 1 (CR1) and 2 (CR2). We hypothesized that C3-bound Ag might cross-link CR2 and/or CR1 with surface (s)IgM and alter the signal that would be transduced through sIgM by Ag binding alone. One result of the altered signal could be the rescue of B lymphocytes from apoptosis that would otherwise be induced by the binding of certain types of Ag alone. We find that co-cross-linking of mouse CR2 and CR1 with sIgM rescues both resting B cells and WEHI-231.7 cells from apoptosis induced by sIgM ligation in a fashion similar to that found using soluble mouse CD40 ligand (mCD40L). Anti-CR2/CR1-mediated rescue requires co-cross-linking of the receptors with sIgM, and has an additive effect on mCD40L-mediated apoptosis rescue. Based on these results, it is likely that the CR2/CR1-derived signal is cooperative with T cell-derived signals such as CD40L and interleukin-4.

Animals↗
PubMed1995

The glycosylphosphatidylinositol-anchored CD59 protein stimulates both T cell receptor zeta/ZAP-70-dependent and -independent signaling pathways in T cells.

The glycosylphosphatidylinositol (GPI)-anchored CD59 protein (human protectin) protects cells against complement-induced lysis, binds to CD2 and also transduces activation signals within T cells. We have further examined the biochemical signals transduced by CD59 and addressed its role in regard to the CD3-mediated signaling cascade. We show here that CD59 cross-linking induces a time-dependent activation of p56lck and of p70zap (ZAP-70) in CD3-positive Jurkat cells, leading to the stimulation of the T cell receptor zeta/ZAP-70 signaling cascade and interleukin-2 (IL-2) synthesis. Cross-linking of CD59 on peripheral T cells and thymocytes induces tyrosine phosphorylations identical to those seen in Jurkat cells and this is followed by lymphokine production and proliferation. In contrast, only activation of CD59-associated p56lck occurs in CD3-negative Jurkat cells, while IL-2 production is impaired, consistent with the lack of ZAP-70 tyrosine phosphorylation observed in these cells. CD59 triggers activation events even in the absence of CD3/T cell receptor expression in Jurkat cells. CD59 cross-linking synergizes with sub-optimal doses of phorbol ester for activation of the protein kinase C and of the p42mapk, as shown by in vitro phosphorylation of histone HIIIS and myelin basic protein, respectively, and leads to CD25 but not CD69 expression. In conclusion, at least two signaling pathways are triggered through CD59, the first one involving ZAP-70 activation and leading to IL-2 secretion and a second pathway observed in the absence of ZAP-70 activation leading to CD25 expression. These two pathways are likely to be involved in the modulation of T cell activation by CD59 protein.

Antigens, CD↗
PubMed1995

Superantigens initiate cognate CD4+ T cell/B cell interactions leading to early activation and proliferation of B cells.

Dimerization or even multimerization of various receptors is commonly required for signal transduction. We report here that clustering of major histocompatibility complex class II molecules in human B cells by biotinylated staphylococcal enterotoxin A (SEA) cross-linked with avidin induces an increase in the level of intracellular calcium. This response was abolished by prior treatment with protein tyrosine kinase (PTK) inhibitors, suggesting that SEA-triggered calcium mobilization in B cells is probably dependent on the activation of PTK. The implication of PTK in SEA-induced early B cell activation was then confirmed by demonstrating that cross-linked SEA induces a significant increase in the level of tyrosine phosphorylation in B cells. The requirement of biotinavidin cross-linking in SEA-induced calcium mobilization in B cells can be fulfilled by the addition CD4+ T cells, suggesting a role for CD4 molecules. Using the murine CD4- T cell hybridoma 3DT, or its derivative I1B3 transfected with human CD4 that both express SEA-specific TCR, we confirmed the CD4 requirement for B cell calcium mobilization and that both specific TCR and CD4 molecules are required in early events of B cell activation induced by SEA. The role of CD4 in SEA-induced B cell proliferation was then investigated. SEA-stimulated B cells proliferated in the presence of CD4+ T cells, whereas no response was observed in the presence of CD8+ T cells. The addition of clone I1B3 CD4+ T cells failed to fulfill the requirement of CD4+ T cells in SEA-induced B cell proliferation, indicating the possible involvement of other CD4+ T cell surface molecules in this response. This issue is currently under investigation.

B-Lymphocytes↗
PubMed1996

Differential modulation of cyclin-dependent kinase inhibitor p27Kip1 by negative signaling via the antigen receptor of B cells and positive signaling via CD40.

The cross-linking of surface immunoglobulins (sIg) of B cells can transmit a negative signal, resulting in cell cycle arrest, apoptosis or both. Signaling via the B cell antigen CD40 reverses the sIg-mediated negative signaling and induces activation and proliferation of B cells. We investigated the molecular mechanism for cell cycle regulation by negative and positive signaling via sIg and CD40, respectively, by using the B cell line WEHI-231. Cross-linking of sIg almost completely reduced the activity of cyclin-dependent kinase (Cdk) 2, essential for cell cycle progression in the late G1 phase, although the level of Cdk2 was not reduced. Among the factors that regulate Cdk2 activation, the activity of the Cdk-activating kinase (CAK) appeared intact and cyclin E was reduced only partially in sIg-cross-linked WEHI-231. In contrast, sIg cross-linking induced a significant Cdk inhibitor (CKI) activity. Since a 27-kDa protein was co-precipitated with Cdk2 in anti-Ig-treated, but not untreated WEHI-231, and the CKI activity in anti-Ig-treated WEHI-231 was neutralized by anti-p27Kip1 antibodies, it is most likely that p27Kip1 is responsible for the CKI activity induced by sIg cross-linking. p27Kip1 may thus play a role in growth inhibition of B cells by negative signaling via sIg. In contrast, CD40 signaling enhanced Cdk2 activity and reduced the p27Kip1 level in anti-Ig-treated WEHI-231, suggesting that the reduction of p27Kip1 plays an important role in the abrogation of sIg-mediated growth arrest by CD40 signaling. Taken together, p27Kip1 is likely to be a crucial target molecule of the negative signaling via sIg and the positive signaling via CD40 essential for T cell-dependent immune responses.

B-Lymphocytes↗
PubMed1997

Integrin alpha chain cytoplasmic tails regulate "antibody-redirected" cell adhesion, independently of ligand binding.

Here we describe a novel "antibody-redirected cell adhesion" (ARCA) assay. This assay measures heterotypic cell-cell adhesion, resulting from antibody bridging between Fc gamma receptors type II (CD32) on leukocytes, and clustered integrins on adherent cell monolayers. This ARCA activity, facilitated by integrins alpha3 beta1 or alpha4 beta1, required an intact cytoskeleton, but did not involve typical integrin ligand binding sites or divalent cations. Furthermore, deletion of the alpha4 cytoplasmic tail almost completely abrogated integrin ARCA activity, suggesting an alteration of integrin recruitment into adhesive sites. If two or more tail residues were present after the conserved GFFKR motif, then ARCA activity was largely restored. Although alpha4 tail deletion caused loss of ARCA activity, it had no effect on the binding of VCAM-1 to intact alpha4-transfected K562 cells. In conclusion, the integrin alpha chain tail can positively regulate integrin-dependent cell adhesion by a receptor recruitment/clustering mechanism independent of conventional integrin ligand-binding considerations.

Actin Cytoskeleton↗
PubMed1997

Regulatory role of CD95 ligation on human B cells induced in vivo capable of spontaneous and high-rate Ig secretion.

CD95 ligation elicits apoptotic signals in many cell systems. This study analyzes the effect of anti-CD95 mAb on human cells capable of spontaneous and high-rate Ig secretion. Such cells have been induced in vivo and represent a highly mature B cell stage. Addition of the anti-CD95 monoclonal antibody (mAb) CH11 to tonsil B cells inhibited 50-60% of their spontaneous Ig secretion. The effect was exerted early in the culture and could be reversed by a pre-treatment with a neutralizing mAb. N-acetyl-D-sphingosine (C2-ceramide), although not a close analog, also reduced Ig secretion to a similar extent. The inclusion of a tetrapeptide inhibitor for certain interleukin-1beta-converting enzyme proteases prevented the inhibitory effect of CH11 mAb on tonsil B cells. B cells capable of spontaneous Ab secretion obtained from blood of recently-immunized volunteers were also inhibited by CH11 mAb and C2-ceramide. In contrast, bone marrow (BM) B cells capable of spontaneous Ig secretion were unaffected by these agents. This CD95 ligation-mediated inhibition of tonsil and blood Ig-secreting B cells could not be reversed by cytokines with demonstrated activity on these B cells. Human mature B cells induced in vivo are identifiable as CD38hi cells. Flow cytometric analysis revealed that a fraction of tonsil CD38hi cells expressed low levels of CD95. Moreover, about 20% of these cells exhibited basal apoptosis, as defined by annexin V binding. This phenomenon was markedly increased by CD95 ligation. On the other hand, BM CD38hi cells showed neither CD95 expression nor CD95-induced annexin V binding. These data suggest that CD95 ligation might play a role in the control of human humoral responses by inducing apoptosis in susceptible mature B cells.

ADP-ribosyl Cyclase↗
PubMedDate not supplied

Intracellular processing of human vs. rat immunoglobulin A in the rat liver.

It is well established that in the rat, rat dimeric IgA is transported from blood to bile across rat liver parenchymal cells via a series of minute smooth membrane-limited vesicles. This pathway is unique from that taken by a number of other ligands, which are internalized for degradation, in that there appears to be little involvement of coated vesicles, multivesicular bodies and lysosomes. The transmembrane receptor for IgA, secretory component, is not recycled but is secreted in part with the ligand into bile and must be produced continuously within the liver cell. Several recent studies have suggested that the receptor for asialoglycoproteins, as well as the structures involved in its processing, may play an important role in IgA processing. It was noted, however, that in all of these studies human polymeric IgA1 was used in the rat model. Using purified rat and human IgA preparations, we have demonstrated by light and quantitative electron microscopic autoradiography, as well as by certain biochemical procedures, that the two ligands are processed quite differently from one another in the rat. Human IgA disappears from the plasma at a slower rate and is much less efficiently transported into the bile. In addition, up to as much as 30% of the human IgA is diverted to the lysosomal pathway. This diversion of human polymeric IgA may be related to either the association of a serine-linked oligosaccharide at the hinge region of the human polymeric IgA1 or that large polymers, often found in human IgA preparations may initiate secretory component receptor aggregation, which in turn, interferes with the normal physiological processing of the IgA molecule.

Animals↗
PubMed1993

The (YXXL/I)2 signalling motif found in the cytoplasmic segments of the bovine leukaemia virus envelope protein and Epstein-Barr virus latent membrane protein 2A can elicit early and late lymphocyte activation events.

The cytoplasmic domains of the transducing subunits associated with B and T cell antigen receptors contain a common amino acid motif consisting of two precisely spaced Tyr-X-X-Leu/Ile sequences (where X corresponds to a variable residue). Expression of a single copy of this motif suffices to initiate B or T cell activation. The bovine leukaemia virus (BLV) is a B cell lymphotropic retrovirus which causes a non-neoplasic proliferation of B cells. The cytoplasmic domain of the BLV transmembrane envelope glycoprotein, gp30, possesses two overlapping copies of the Tyr-X-X-Leu/Ile-containing motif which could participate in the induction of B cell activation. Similarly, the N-terminal cytoplasmic domain of the latent membrane protein 2A (LMP2A) of the Epstein-Barr virus (EBV) contains a single copy of the Tyr-X-X-Leu/Ile-containing motif which could play a critical role in B cell transformation. To determine whether these two virus-encoded cytoplasmic domains are endowed with signalling functions, we constructed chimeric proteins by replacing the cytoplasmic tail of CD8-alpha with that of either BLV gp30 or EBV LMP2A. We show here that, once separately expressed in B or T cell lines, these chimeras are capable of triggering both calcium responses and cytokine production when cross-linked with an antibody to CD8-alpha. Furthermore, using site-directed mutagenesis, we demonstrated unequivocally that this signalling function may be accounted for by the Tyr-X-X-Leu/Ile motifs they contain.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1995

Reconstitution of interactions between tyrosine kinases and the high affinity IgE receptor which are controlled by receptor clustering.

High affinity IgE receptor (Fc epsilon RI) signaling after contact with antigen occurs in response to receptor clustering. This paper describes methodology, based on vaccinia virus driven protein expression, for probing signaling pathways and its application to Fc epsilon RI interactions with the lyn and syk tyrosine kinases. Reconstitution of the complete tetrameric Fc epsilon RI receptor, lyn and syk in a non-hematopoietic 'null' cell line is sufficient to reconstruct clustering-controlled receptor tyrosine phosphorylation and activation of syk, without apparent requirement for hematopoietic specific phosphatases. The src family kinase lyn phosphorylates Fc epsilon RI in response to receptor clustering, resulting in syk binding to the phosphorylated Fc epsilon RI. Lyn also participates in the tyrosine phosphorylation and activation of syk in a manner which is dependent on phosphorylated Fc epsilon RI. Using overexpression of active and dominant negative syk proteins in a mast cell line which naturally expresses Fc epsilon RI, we corroborate syk's role downstream of receptor phosphorylation, and demonstrate that syk SH2 domains protect receptor ITAMs from ongoing dephosphorylation. Based on these results, we propose that receptor clustering controls lyn-mediated Fc epsilon RI tyrosine phosphorylation by shifting a balance between phosphorylation and dephosphorylation towards accumulation of tyrosine phosphorylated Fc epsilon RI. Fc epsilon RI tyrosine phosphorylation functions to bring syk into a microenvironment where it becomes tyrosine phosphorylated and activated, thereby allowing clustering to indirectly control syk activity.

3T3 Cells↗