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PubMed1986

Leukocyte aggregation response to quantitative plasma levels of C3a and C5a.

Granulocyte aggregation (GA) response has previously been described as a sensitive assay for complement activation in sepsis. Complement component C5a has been implicated as the plasma factor responsible for GA. The quantitative interaction of complement components C3a and C5a with GA, however, is not clearly defined. This study evaluates the relationship of GA responses to plasma levels of C5a and C3a in zymosan-activated plasma (ZAP). The C3a and C5a levels were measured by radioimmunoassay in serial dilutions of ZAP. Granulocyte aggregation responses of normal human leukocytes were determined for each ZAP dilution. The C5a levels in a 1:16 dilution of ZAP were higher than in normal plasma (22 +/- 7 vs 9 +/- 3 ng/mL), as were GA responses (24 +/- 1 vs 11 +/- 2 percentage of maximum light transmission). The C3a levels in a 1:8 dilution of ZAP are elevated above those of normal plasma (656 +/- 167 vs 411 +/- 29 ng/mL). Correlation coefficients were .9809 for C3a vs GA, .9788 for C5a vs G, and .9860 for C3a vs C5a. Complement components C3a and C5a are involved in GA in vitro. Granulocyte aggregometry can detect low levels of activated complement in ZAP but may not be specific for C5a. The relative contribution of C3a and C5a to observed GA is not clear from the data.

Cell Aggregation↗
PubMed1991

Characterization of arachidonic acid metabolism, superoxide production, and bacterial killing by bovine alveolar neutrophils elicited with leukotriene B4 and zymosan-activated plasma.

Leukotriene B4 (LTB4) and zymosan-activated plasma (ZAP) were each instilled into the lungs of steers to elicit alveolar neutrophils for subsequent functional analysis. Prior to instillation of either agent, bronchoalveolar lavage cell populations consisted of 95.8 +/- 0.4% macrophages (mean +/- SEM). Four hours after instillation of LTB4 or ZAP, the lavage cell populations consisted of 75.0 +/- 8.8% and 90.7 +/- 0.7% neutrophils, respectively. Alveolar neutrophils elicited with LTB4 and stimulated with the calcium ionophore A23187 released diminished amounts of LTB4 and increased amounts of 5-hydroxyeicosatetraenoic acid (5-HETE) as compared to circulating neutrophils. Release of superoxide anion was decreased for LTB4-elicited alveolar neutrophils as compared to circulating cells, while bacterial killing was unchanged. ZAP-elicited alveolar neutrophils released diminished amounts of LTB4 when stimulated with A23187 as compared to circulating neutrophils. There were no differences observed in 5-HETE levels between the two cell populations. In addition, release of superoxide anion was diminished among ZAP-elicited alveolar cells, while bacterial killing was unchanged. Incubation of circulating neutrophils with LTB4 did not influence the release of arachidonate metabolites, superoxide anion, or bacterial killing. However, incubation of circulating neutrophils with ZAP, followed by A23187 resulted in a reduction in the release of LTB4, as compared to control cells. Prior exposure to ZAP did not influence the release of superoxide anion or bacterial killing by the circulating neutrophils.

Animals↗
PubMed2001

The Z-line appearance and prevalence of intestinal metaplasia among patients without symptoms or endoscopical signs indicating gastroesophageal reflux.

BACKGROUND: A four-graded classification of the Z-line appearance (ZAP) has been proposed, which was shown to correlate with the prevalence of intestinal metaplasia (IM) among patients with gastroesophageal reflux disease (GERD). The aim of this study was to determine the ZAP grade and the prevalence of IM among patients without GERD. METHODS: In this study, 53 consecutive patients without signs or symptoms of GERD were included. RESULTS: A normal Z-line (ZAP grade 0) was found in 26 patients (51%), and this group had a lower prevalence of Helicobacter pylori infection and atrophy in the cardia than ZAP grade patients. The non-GERD patients in this study had less ZAP pathology than the GERD patients in our previous study. Intestinal metaplasia at the Z-line, observed in 17% of the patients, was found to associate with peptic ulcer and carditis. CONCLUSION: The normal Z-line is feasibly defined as ZAP grade 0.

Adult↗
PubMed1999

Protective effects of poly (ADP-ribose) synthase inhibitors in zymosan-activated plasma induced paw edema.

The aim of the present study was to investigate the role of poly (ADP-ribose) synthetase (PARS) in a model of acute local inflammation (zymosan-activated plasma (ZAP)-induced paw edema), in which the oxyradicals, nitric oxide and peroxynitrite, are known to play a crucial role. Injection of zymosan-activated plasma (ZAP) into the rat paw induced edema formation. The maximal increase in paw volume was observed at three hours after administration (maximal in paw volume: 1.29+/-0.09 ml). At this time point, there was a marked increase in neutrophil infiltration in the paw, as measured by an increase in myeloperoxidase (MPO) activity in the paw tissue (260+/-25 mU/100 mg wet tissue). However, ZAP-induced paw edema was significantly reduced in a dose-dependent manner by treatment with 3-aminobenzamide (3-AB) or nicotinamide (NIC), two inhibitors of PARS, at 1, 2, 3, 4 hours after ZAP injection. PARS inhibition also caused a significant reduction of MPO activity. The paw tissues were also examined immunohistochemically for the presence of nitrotyrosine (a footprint for peroxynitrite formation). At 3 h following ZAP injection, staining for nitrotyrosine were also found to be localised within discrete cells in the inflamed paw tissue. Treatment with PARS inhibitor prevented the appearance of nitrotyrosine in the tissues. Our results suggest that in paw edema induced by ZAP, inhibition of PARS exert potent anti-inflammatory effects.

Animals↗
PubMed1997

Cyclic GMP decreases cardiac myocyte oxygen consumption to a greater extent under conditions of increased metabolism.

We tested the hypothesis that the negative effects of intracellular guanosine 3',5'-cyclic monophosphate (cyclic GMP) were more profound on cardiac myocyte oxygen consumption (VO2) during increased metabolism of the myocytes. The steady state VO2 of a suspension of single myocytes isolated from hearts of New Zealand White rabbits was measured in a glass chamber by using a Clark-type oxygen electrode, and cyclic GMP was determined by using a radioimmunoassay. The cellular cyclic GMP levels were increased either by adding 3-morpholino-sydnonimine (SIN-1), a guanylate cyclase stimulator, or zaprinast (ZAP), a cyclic GMP-phosphodiesterase inhibitor, at various doses. In 0.5 mM Ca2+ medium, average VO2 was 123 +/- 8 nl/min/100,000 cells, and cyclic GMP was 35.4 +/- 9.3 fmol/100,000 cells, and these increased significantly to 182 +/- 9 nl/min/100,000 cells and 78.2 +/- 7.3 fmol/100,000 cells in 2.0 mM Ca2+. There were dose-dependent responses of the VO2 and cellular cyclic GMP levels in responding to both SIN-1 and ZAP. An inverse relation between cellular cyclic GMP level and VO2 existed in the myocytes. The regression equations for the four treatments were log(VO2) = -0.002[cyclic GMP] + 2.19, r = 0.96 for SIN-1 in low (0.5 mM) Ca2+; log(VO2) = 0.005[cyclic GMP] + 1.80, r = 0.38 for ZAP in low Ca2+; log(VO2) = -0.001 [cyclic GMP] + 2.24, r = 0.82 for SIN-1 in high (2.0 mM) Ca2+; and log(VO2) = -0.004[cyclic GMP] + 2.56, r = 0.93 for ZAP in high Ca2+. The slope of ZAP regression line was significantly more negative than that of SIN-1 with high calcium. At any given level of cyclic GMP, ZAP decreased the VO2 to a greater extent than did SIN-1 although the latter caused the maximal increase in cyclic GMP level. The reduction in VO2 caused by a corresponding increase in cellular cyclic GMP was greater in myocytes incubated with high-Ca2+ medium.

Animals↗
PubMed2001

A postfundoplication study on Z-line appearance and intestinal metaplasia in the gastroesophageal junction.

The purpose of this study was investigate the Z-line appearance by using a previously proposed classification, the ZAP classification, and to investigate the prevalence of intestinal metaplasia in the Z-line, among fundoplicated patients. Sixty patients, who had undergone fundoplication 2 to 17 years earlier, were included in the study. The prevalence of intestinal metaplasia was 20%. Intestinal metaplasia was found to be associated with age, more than 10 years of symptoms of gastroesophageal reflux disease preoperatively, tongues of columnar epithelium in the distal esophagus, carditis, and ZAP grade. ZAP grade, furthermore, was associated with male gender and more than 10 years of symptoms of gastroesophageal reflux disease preoperatively. Among patients with intestinal metaplasia, different ZAP grades can indicate different etiologic factors. Even among patients undergoing fundoplication (i.e., patients with an anatomically altered gastroesophageal junction), the ZAP classification is a feasible tool to characterize the Z-line appearance. The ZAP classification could prove valuable in selecting patients for follow-up treatment.

Adult↗
PubMed2004

The zinc finger antiviral protein directly binds to specific viral mRNAs through the CCCH zinc finger motifs.

The zinc finger antiviral protein (ZAP) is a recently isolated host antiviral factor. It specifically inhibits the replication of Moloney murine leukemia virus (MLV) and Sindbis virus (SIN) by preventing the accumulation of viral RNA in the cytoplasm. For this report, we mapped the viral sequences that are sensitive to ZAP inhibition. The viral sequences were cloned into a luciferase reporter and analyzed for the ability to mediate ZAP-dependent destabilization of the reporter. The sensitive sequence in MLV was mapped to the 3' long terminal repeat; the sensitive sequences in SIN were mapped to multiple fragments. The fragment of SIN that displayed the highest destabilizing activity was further analyzed by deletion mutagenesis for the minimal sequence that retained the activity. This led to the identification of a fragment of 653 nucleotides. Any further deletion of this fragment resulted in significantly lower activity. We provide evidence that ZAP directly binds to the active but not the inactive fragments. The CCCH zinc finger motifs of ZAP play important roles in RNA binding and antiviral activity. Disruption of the second and fourth zinc fingers abolished ZAP's activity, whereas disruption of the first and third fingers just slightly lowered its activity.

Amino Acid Motifs↗
PubMed1991

Neutrophil-associated lung injury after the infusion of activated plasma.

Previous studies from our laboratory have shown that the infusion of zymosan-activated plasma (ZAP) caused large numbers of neutrophils (PMN) to accumulate in the lung. Although PMN are known to be activated by ZAP, it is unclear whether PMN delayed in the lung by ZAP infusion actually cause lung injury. The present study was designed to examine this question by measuring airway epithelial and endothelial injury. Airway epithelial injury was determined by depositing a known dose of fluorescein isothiocyanate-labeled dextran in the lung and measuring its appearance in the blood, and endothelial injury was measured by injecting colloidal carbon and measuring its accumulation in the microvasculature of the lung. The data show that ZAP infusion caused a mild epithelial and endothelial injury that did not increase either extravascular water or protein. This injury could be prevented either by depleting the animals of PMN or by pretreating them with indomethacin. In addition, the effect of ZAP infusion could be partially restored by transfusing donor PMN into the PMN-depleted animals. We conclude that ZAP infusion produces a mild lung injury that is dependent on PMN and the products of the cyclooxygenase pathway of arachidonic acid metabolism.

Animals↗
PubMed1992

Effect of zymosan-activated plasma on the deformability of rabbit polymorphonuclear leukocytes.

Intravascular infusion of inflammatory mediators causes a sudden neutropenia due to the sequestration of polymorphonuclear leukocytes (PMN) within the microvasculature of the lung and other organs. This sequestration could be due to a decrease in the ability of PMN to deform and pass through the narrow capillary bed. The purpose of this study was to determine if the complement fragments present in zymosan-activated plasma (ZAP) caused a rapid stiffening of PMN. The PMN deformability was determined by measuring the pressure required to pass PMN through a polycarbonate filter containing 5-micron pores at a constant flow rate as well as the extraction of PMN compared with red blood cells and 125I-labeled albumin by the filter. The role of the cytoskeleton in PMN deformation was examined in studies where F-actin formation was inhibited using cytochalasin B or microtubule assembly was inhibited using colchicine. The results showed that treatment with ZAP induced a rapid decrease in PMN deformability. Inhibiting the formation of F-actin made the unstimulated PMN more deformable and reduced the stiffening induced by ZAP. In contrast, inhibition of microtubule reassembly did not alter either normal deformability or the ZAP-induced decrease in deformability. In vivo, colchicine increased normal PMN margination but did not inhibit the rapid sequestration of PMN induced by infusion of ZAP. These studies indicate that ZAP induces a rapid decrease in PMN deformability that is mediated through the cytoskeleton. They suggest that this decrease is due to the polymerization of F-actin.

Actins↗
PubMed2003

SWAP-70-like adapter of T cells, an adapter protein that regulates early TCR-initiated signaling in Th2 lineage cells.

We describe the isolation of a protein, SWAP-70-like adapter of T cells (SLAT), which is expressed at high levels in thymocytes and differentiated Th2 cells. SLAT expression was upregulated in differentiating Th2 cells and downregulated in Th1 cells. Ectopic SLAT expression exerted positive or negative effects on IL-4 versus IFNgamma induction, respectively. TCR signaling induced translocation of SLAT to the immunological synapse and its association with ZAP-70 kinase. SLAT reduced the association of ZAP-70 with TCR-zeta and interfered with ZAP-70 but not Lck signaling. Consistent with these results, pharmacological inhibition of ZAP-70 also induced Th2 skewing. Thus, SLAT is a protein which plays a role in Th2 development and/or activation, perhaps by interfering with ZAP-70 signaling.

Amino Acid Sequence↗
PubMed1999

Interaction between CD45-AP and protein-tyrosine kinases involved in T cell receptor signaling.

CD45-AP associates specifically with CD45, a protein-tyrosine phosphatase essential for antigen receptor-mediated signal transduction. CD45 modulates the activity of Src family protein-tyrosine kinases involved at the onset of antigen receptor-mediated signaling by dephosphorylating their regulatory tyrosyl residues. We have shown that lymphocyte responses to antigen receptor stimulation are impaired in CD45-AP-null mice. To examine the possibility that CD45-AP coordinates the interaction between CD45 and its substrates, we investigated the associations of CD45-AP with several protein-tyrosine kinases. Endogenous CD45-AP coimmunoprecipitated with Lck and ZAP-70 in both CD45-positive T cells and their CD45-negative variants after stimulation by antigen receptor ligation. Concomitantly, CD45 coimmunoprecipitated with Lck and ZAP-70 after T cell receptor-mediated stimulation of CD45-positive cells. Recombinant CD45-AP exhibited specific binding to Lck and ZAP-70 protein-tyrosine kinases, but not to Fyn or Csk, in lysates of both CD45-positive and -negative T cells. Specific interactions were demonstrated between the respective recombinant proteins as well. These results demonstrate that CD45-AP associates directly and selectively with Lck and ZAP-70 in response to T cell receptor-mediated stimulation. The associations of CD45-AP with Lck and ZAP-70 may mediate the functional interactions of these kinases with CD45 during antigen receptor stimulation.

Animals↗
PubMed1998

Dissociation of intracellular signaling pathways in response to partial agonist ligands of the T cell receptor.

The T cell receptor (TCR) is a versatile receptor able to generate different signals that result in distinct T cell responses. The pattern of early signals is determined by the TCR binding kinetics that control the ability of the ligand to coengage TCR and coreceptor. Coengagement of TCR and CD4 results in an agonist signaling pattern with complete tyrosine phosphorylation of TCR subunits, and recruitment and activation of ZAP-70. In contrast, TCR engagement without CD4 coengagement causes a partial agonist type of signaling, characterized by distinct phosphorylation of TCR subunits and recruitment but no activation of ZAP-70. The pathways triggered by partial agonist signaling are unknown. Here, we show that agonists cause association of active lck and active ZAP-70 with p120-GTPase-activating protein (p120-GAP). These associations follow engagement of CD4 or CD3, respectively. In contrast, partial agonists do not activate lck or ZAP-70, but induce association of p120-GAP with inactive ZAP-70. Despite these differences, both agonist and partial agonist signals activate the mitogen-activated protein kinase (MAPK) pathway. However, MAPK activation by partial agonists is transient, supporting a kinetic, CD4-dependent model for the mechanism of action of variant TCR ligands. Transient MAPK activation may explain some of the responses to TCR partial agonists and antagonists.

Animals↗
PubMed1999

Altered expression of tyrosine kinases of the Src and Syk families in human T-cell leukemia virus type 1-infected T-cell lines.

During the late phase of adult T-cell leukemia/lymphoma, a severe lymphoproliferative disorder caused by human T-cell leukemia virus type 1 (HTLV-1), leukemic cells no longer produce interleukin-2. Several studies have reported the lack of the Src-like protein tyrosine kinase Lck and overexpression of Lyn and Fyn in these cells. In this report we demonstrate that, in addition to the downregulation of TCR, CD45, and Lck (which are key components of T-cell activation), HTLV-1-infected cell lines demonstrate a large increase of FynB, a Fyn isoform usually poorly expressed in T cells. Furthermore, similar to anergic T cells, Fyn is hyperactive in one of these HTLV-1-infected T-cell lines, probably as a consequence of Csk downregulation. A second family of two proteins, Zap-70 and Syk, relay the signal of T-cell activation. We demonstrate that in contrast to uninfected T cells, Zap-70 is absent in HTLV-1-infected T cells, whereas Syk is overexpressed. In searching for the mechanism responsible for FynB overexpression and Zap-70 downregulation, we have investigated the ability of the Tax and Rex proteins to modulate Zap-70 expression and the alternative splicing mechanism which gives rise to either FynB or FynT. By using Jurkat T cells stably transfected with the tax and rex genes or inducibly expressing the tax gene, we found that the expression of Rex was necessary to increase fynB expression, suggesting that Rex controls fyn gene splicing. Conversely, with the same Jurkat clones, we found that the expression of Tax but not Rex could downregulate Zap-70 expression. These results suggest that the effect of Tax and Rex must cooperate to deregulate the pathway of T-cell activation in HTLV-1-infected T cells.

Down-Regulation↗
PubMed1997

Regulation of T-cell antigen receptor signalling by Syk tyrosine protein kinase.

T-cell antigen receptor (TCR) signalling has been shown to involve two classes of tyrosine protein kinases: the Src-related kinases p56(lck) and p59(fyr), and the Zap-70/Syk family kinases. Lck and FynT are postulated to initiate TCR-triggered signal transduction by phosphorylating the CD3 and zeta subunits of the TCR complex. This modification permits the recruitment of Zap-70 and Syk, which are presumed to amplify the TCR-triggered signal, by phosphorylating additional intracellular proteins. While Zap-70 is expressed in all T cells, Syk is present in thymocytes and mature T-cell populations such as intraepithelial gammadelta T cells and naive alphabeta T cells. To better understand the role of Syk in these cells, its impact on the physiology of an antigen-specific T-cell line was tested. Our results showed that compared to Zap-70 alone, Syk was a strong positive regulator of antigen receptor-induced signals in BI-141 cells. Surprisingly, they indicated that, like Src family kinases, Syk augmented TCR-triggered tyrosine phosphorylation of CD3/zeta. Syk, but not Zap-70 alone, could also stimulate tyrosine phosphorylation of a zeta-bearing chimera in transiently transfected Cos-1 cells. Finally, evidence was provided that Syk has the capacity to directly phosphorylate a zeta-derived peptide in vitro. These findings suggested that Syk may have a unique role in T cells, as a consequence of its ability to efficiently phosphorylate multiple components of the TCR signalling cascade. Furthermore, they raised the possibility that Syk can regulate the initiation of TCR signalling, by promoting phosphorylation of the immunoreceptor tyrosine-based activation motifs of the TCR complex.

Animals↗
PubMed2000

Differential T-cell antigen receptor signaling mediated by the Src family kinases Lck and Fyn.

Src family tyrosine kinases play a key role in T-cell antigen receptor (TCR) signaling. They are responsible for the initial tyrosine phosphorylation of the receptor, leading to the recruitment of the ZAP-70 tyrosine kinase, as well as the subsequent phosphorylation and activation of ZAP-70. Molecular and genetic evidence indicates that both the Fyn and Lck members of the Src family can participate in TCR signal transduction; however, it is unclear to what extent they utilize the same signal transduction pathways and activate the same downstream events. We have addressed this issue by examining the ability of Fyn to mediate TCR signal transduction in an Lck-deficient T-cell line (JCaM1). Fyn was able to induce tyrosine phosphorylation of the TCR and recruitment of the ZAP-70 kinase, but the pattern of TCR phosphorylation was altered and activation of ZAP-70 was defective. Despite this, the SLP-76 adapter protein was inducibly tyrosine phosphorylated, and both the Ras-mitogen-activated protein kinase and the phosphatidylinositol 4, 5-biphosphate signaling pathways were activated. TCR stimulation of JCaM1/Fyn cells induced the expression of the CD69 activation marker and inhibited cell growth, but NFAT activation and the production of interleukin-2 were markedly reduced. These results indicate that Fyn mediates an alternative form of TCR signaling which is independent of ZAP-70 activation and generates a distinct cellular phenotype. Furthermore, these findings imply that the outcome of TCR signal transduction may be determined by which Src family kinase is used to initiate signaling.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Defective development of NK1.1+ T-cell antigen receptor alphabeta+ cells in zeta-associated protein 70 null mice with an accumulation of NK1.1+ CD3- NK-like cells in the thymus.

Development of natural killer 1.1+ (NK1.1+) CD3+ (NK1.1+ T) cells was analyzed in zeta-associated protein 70 (ZAP-70) null ((-/-)) mice. Both NK1.1+ TCRalphabeta+ and NK1.1+ TCRgammadelta+ cell populations were absent in the thymus and spleen. By contrast, the number of NK1.1+ CD3- cells was increased in these tissues. The NK1.1+ CD3- thymocytes in ZAP-70(-/-) mice had surface phenotypes in common with NK or NK1.1+ T cells. However, some of them were discordant either with NK cells or with NK1.1+ T cells. The NK1.1+ CD3- cells produced interferon-gamma upon stimulation with NK1.1 cross-linking in the presence of interleukin-2 and exhibited a substantial cytotoxicity against YAC-1 cells. Moreover, the generation of NK1.1+ T cells with invariant Valpha14Jalpha281 chains was induced from the NK1.1+ CD3- thymocytes following stimulation with phorbol myristate acetate and ionomycin in a neonatal thymic organ culture. An introduction of TCRalpha and beta transgenes to the ZAP-70(-/-) mice resulted in generation of an NK1.1+ TCRalphabeta(dim) population, whereas no substantial CD4+ CD8- or CD4- CD8+ population that expressed the introduced TCRalphabeta was generated in the mainstream T lineage. These findings demonstrate that ZAP-70 kinase is indispensable for the development of NK1.1+ T cells and that the unique NK1.1+ CD3- thymocytes in ZAP-70(-/-) mice contain immediate precursors of NK1.1+ T cells.

Animals↗
PubMed1992

Infusion of zymosan-activated plasma affects neutrophils in peripheral blood and bone marrow in sheep.

Intravenous infusion of zymosan-activated plasma (ZAP) in sheep results in acute lung injury mediated in part by free radical release from stimulated neutrophils that are retained in increased numbers in the pulmonary microcirculation. ZAP infusion is also associated with long-term reduction in elicited superoxide anion generation from segmented neutrophils in the circulating and bone marrow pools for at least 24 h after the infusion. The purpose of our study was to investigate the effect of ZAP infusion on leukocyte counts and neutrophil granule-associated enzyme activity in the circulating and bone marrow pools. Cytochemical methods were used to characterize enzyme activity in primary granules (acid phosphatase and myeloperoxidase) and secondary granules (alkaline phosphatase). During the infusion period, neutrophil differential counts decreased less in venous blood than in matched arterial blood. Release from bone marrow stores was evident as increased numbers of circulating band neutrophils during and after the infusion. Neutrophils in venous and arterial blood smears were degranulated acutely during and 1-3 h after the infusion was stopped. Band and segmented neutrophils in bone marrow also appeared slightly degranulated 1-2 h after the infusion. In vitro experiments showed that band and segmented neutrophils in bone marrow degranulated in response to ZAP incubation. Immature polymorphonuclear leukocytes did not degranulate. Five to 24 h after ZAP infusion, enzyme activity in circulating and bone marrow neutrophils was at baseline levels, suggesting that new cells were being released into the circulating pool because degranulated neutrophils do not synthesize new granules. Another indication of a long-term effect in bone marrow were slight decreases in the percentage of immature polymorphonuclear leukocytes and band neutrophils and a significant decrease in the percentage of eosinophils, all of which coincided with a significant increase in the percentage of segmented neutrophils. Our results demonstrate that circulating complement anaphylatoxins affect neutrophils in bone marrow as well as the vascular space.

Anesthesia↗
PubMed1994

Diminished tyrosine protein kinase activity in T cells unresponsive to TCR stimulation.

Tyrosine phosphorylation is thought to be one of the earliest steps in antigenic activation of T cells. Three nonreceptor tyrosine kinases, p56lck, p60fyn, and ZAP-70, are known to be involved in T cell receptor (TCR) signaling, albeit their functional roles appear to be different. Whereas p60fyn and ZAP-70 are functionally associated with the T cell antigen receptor, p56lck is essential for TCR signaling without being directly coupled to the TCR. We have studied a mutant variant of the Jurkat T cell line (J32-3.2), in which basal activities of p56lck and p60fyn are 2- to 2.5-fold reduced relative to those in its parental line (J32) while basal activity of ZAP-70 remains unchanged, and compared responses of J32-3.2 and J32 to TCR stimulation. We have demonstrated that tyrosine phosphorylation following CD3 cross-linking in J32-3.2 cells was extremely short-lived and thus insufficient for the induction of subsequent physiological responses. This was at least partially due to the diminished tyrosine kinase activity in these cells. A decrease in the activity of src-related kinases was caused primarily by their lower expression, whereas expression of ZAP-70 was unchanged but its response to CD3 cross-linking was diminished, correlating with the deficient tyrosine phosphorylation of the CD3 zeta-chain, recently observed in J32-3.2. These data are consistent with the idea that src-related kinases phosphorylate the zeta-chain, which in turn recruits ZAP-70 required to sustain the signal.

CD3 Complex↗