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PubMed1995

The pre-T cell receptor (TCR) complex is functionally coupled to the TCR-zeta subunit.

The pre-T cell receptor (TCR) complex regulates early T cell development and consists of a heterodimer of the TCR-beta subunit in association with the pre-TCR-alpha chain. Notably, in contrast to alpha/beta-expressing T cells, several studies suggested that the TCR-zeta chain is not stably associated with this pre-TCR complex. To examine the proximal signaling processes mediated by the pre-TCR complex and the role of the TCR-zeta chain in these processes, we stimulated pre-TCR-expressing cells and analyzed the interactions of the TCR/CD3 invariant chains with the Syk/ZAP-70 family of protein tyrosine kinases. Stimulation of the pre-TCR complex led to the tyrosine phosphorylation of the CD3 epsilon and TCR-zeta chains, as well as the phosphorylation and association of ZAP-70 and Syk with phosphorylated CD3 epsilon and TCR-zeta. These results demonstrate that the pre-TCR complex is functionally coupled to the TCR-zeta subunit and to the ZAP-70 and Syk protein tyrosine kinases.

Amino Acid Sequence↗
PubMed1996

Differential association of protein tyrosine kinases with the T cell receptor is linked to the induction of anergy and its prevention by B7 family-mediated costimulation.

When stimulated through their antigen receptor, without costimulation, T cells enter a state of antigen-specific unresponsiveness, termed anergy. B7-mediated costimulation, signaling via CD28, is sufficient to prevent the induction of anergy. Here we show that ligation of T cell receptor (TCR) by alloantigen alone, which results in anergy, activates tyrosine phosphorylation of TCR zeta and its association with fyn. In contrast, TCR ligation in the presence of B7 costimulation, which results in productive immunity, activates tyrosine phosphorylation of TCR zeta and CD3 chains, which associate with activated lck and zeta-associated protein (ZAP) 70. Under these conditions, CD28 associates with activated lck and TCR zeta. These data suggest that the induction of anergy is an active signaling process characterized by the association of TCR zeta and fyn. In addition, CD28-mediated costimulation may prevent the induction of anergy by facilitating the effective association of TCR zeta and CD3 epsilon with the critical protein tyrosine kinase lck, and the subsequent recruitment of ZAP-70. Strategies to inhibit or activate TCR-associated, specific protein tyrosine kinase-mediated pathways may provide a basis for drug development with potential applications in the fields of transplantation, autoimmunity, and tumor immunity.

3T3 Cells↗
PubMed1997

Nonmitogenic anti-CD3 monoclonal antibodies deliver a partial T cell receptor signal and induce clonal anergy.

Anti-CD3 monoclonal antibodies (mAbs) are potent immunosuppressive agents used in clinical transplantation. However, the activation-related adverse side effects associated with these mAbs have prompted the development of less toxic nonmitogenic anti-CD3 mAb therapies. At present, the functional and biochemical consequences of T cell exposure to nonmitogenic anti-CD3 is unclear. In this study, we have examined the early signaling events triggered by a nonmitogenic anti-CD3 mAb. Like the mitogenic anti-CD3 mAb, nonnmitogenic anti-CD3 triggered changes in the T cell receptor (TCR) complex, including zeta chain tyrosine phosphorylation and ZAP-70 association. However, unlike the mitogenic anti-CD3 stimulation, nonmitogenic anti-CD3 was ineffective at inducing the highly phosphorylated form of zeta (p23) and tyrosine phosphorylation of the associated ZAP-70 tyrosine kinase. This proximal signaling deficiency correlated with minimal phospholipase Cgamma-1 phosphorylation and failure to mobilize detectable Ca2+. Not only did biochemical signals delivered by nonmitogenic anti-CD3 resemble altered peptide ligand signaling, but exposure of Th1 clones to nonmitogenic anti-CD3 also resulted in functional anergy. Finally, a bispecific anti-CD3 X anti-CD4 F(ab)'2 reconstituted early signal transduction events and induced proliferation, suggesting that defective association of lck with the TCR complex may underlie the observed signaling differences between the mitogenic and nonmitogenic anti-CD3.

Animals↗
PubMed1998

Engagement of T cell receptor triggers its recruitment to low-density detergent-insoluble membrane domains.

T-cell receptors (TCRs) upon binding to peptide-MHC ligands transduce signals in T lymphocytes. Tyrosine phosphorylations in the cytoplasmic domains of the CD3 (gammadeltaepsilon) and zeta subunits of the TCR complex by Src family kinases initiate the signaling cascades via docking and activation of ZAP-70 kinase and other signaling components. We examined the role of the low-density detergent-insoluble membranes (DIMs) in TCR signaling. Using mouse thymocytes as a model, we characterized the structural organization of DIMs in detail. We then demonstrated that TCR engagement triggered an immediate increase in the amount of TCR/CD3 present in DIMs, which directly involves the engaged receptor complexes. TCR/CD3 recruitment is accompanied by the accumulation of a series of prominent tyrosine-phosphorylated substrates and by an increase of the Lck activity in DIMs. Upon TCR stimulation, the DIM-associated receptor complexes are highly enriched in the hyperphosphorylated p23 zeta chains, contain most of the TCR/CD3-associated, phosphorylation-activated ZAP-70 kinases and seem to integrate into higher order, multiple tyrosine-phosphorylated substrate-containing protein complexes. The TCR/CD3 recruitment was found to depend on the activity of Src family kinases. We thus provide the first demonstration of recuitment of TCR/CD3 to DIMs upon receptor stimulation and propose it as a mechanism whereby TCR engagement is coupled to downstream signaling cascades.

Animals↗
PubMed1999

CD44 signaling through p56lck involves lateral association with CD4 in human CD4+ T cells.

CD44 is a family of mucin-like membrane proteins generated by alternative splicing of several exons, and participate in T cell adhesion and activation. CD44-mediated signaling involves activation of p56(lck) and leads to ZAP-70 phosphorylation. The aim of the present study was to identify the signaling pathways that follow CD44-triggered ZAP-70 phosphorylation and the molecular mechanisms underlying the CD44 interaction with p56(lck). We found that CD44 cross-linking by mAb in CD4(+) peripheral blood T cells promotes formation of a trimeric complex of Grb2, phospholipase (PLC)-gamma1 and a 36-38 kDa phosphoprotein, and the activation of PLC-gamma1. The amount of inositol triphosphate and the time kinetics of its generation were comparable to those following CD3 cross-linking. Co-capping, co-immunoprecipitation and fluorescence resonance energy transfer experiments showed that CD44 associates with CD4 and CD3 on the cell surface. This association suggests functional interplay between the CD4-TCR complex and CD44. In line with this possibility, we found that CD4 triggering by gp120, a natural ligand of CD4, potentiates CD44-mediated adhesion to hyaluronic acid. Moreover, Ca2+ mobilization induced by CD44 cross-linking by mAb was higher in a subclone of the HUT78 cell line expressing CD4 than in a non-expressing subclone.

CD4 Antigens↗
PubMed2001

Altered functional and biochemical response by CD8+ T cells that remain after tolerance.

To further define the molecular basis of tolerance to a peripherally expressed antigen we have correlated differences in functional capacity with biochemical events in hemagglutinin (HA)-specific cytotoxic T lymphocyte (CTL) clones derived either from a conventional B10.D2 mouse that is not tolerant to HA (D2 Clone 6) or from an InsHA mouse that is tolerant to HA (InsHA Clone 12). D2 Clone 6, but not InsHA Clone 12, triggers diabetes following in vivo transfer into irradiated InsHA hosts. This diabetogenic clone shows complete and sustained phosphorylation of TCR zeta chain and ZAP-70 following stimulation with HA-pulsed antigen-presenting cells. In contrast, InsHA Clone 12 showed only partial phosphorylation of TCR zeta and no phosphorylation of ZAP-70. There was no defect in activation or recruitment of Lck to the TCR complex in both the clones following stimulation with the cognate antigen. This deficiency in the proximal signaling in the InsHA Clone 12 could be overcome by increasing the strength of signal through the CD3-TCR complex, indicating that the signaling machinery of InsHA Clone 12 was functional. These data demonstrate that the HA-responsive CD8(+) T cells that can be retrieved from InsHA mice after tolerance induction respond to HA as a partial agonist/antagonist.

Animals↗
PubMed2005

Differential control of G0 programme in chronic lymphocytic leukaemia: a novel prognostic factor.

Chronic lymphocytic leukaemia (CLL) is a unique malignancy where quiescent B cells accumulate in the peripheral blood. Since clinical outcomes in CLL are very heterogeneous, it is of utmost importance to correctly assess the disease prognosis in each individual case. Recently, it has been shown that high ZAP-70 [Zeta-chain (T-cell receptor) associated protein kinase (70 kDa)] expression level strongly correlates with lack of IgV(H) mutations and poor prognosis in B-CLL. As CLL malignant cells are arrested in G(0), we investigated whether Dipeptidyl Peptidase 2 (DPP2), a serine protease that plays a key role in keeping cells in the quiescent state, is involved in cell-cycle control in CLL. We have previously shown that specific inhibition of DPP2 results in apoptosis of normal lymphocytes. In this study, cell apoptosis experiments were conducted in 38 patients with B-CLL. Two distinct subsets of B-CLL were identified, susceptible and resistant to DPP2-inhibition-induced apoptosis. If resistant to apoptosis (42.1%), the CLL cells have higher expression of ZAP-70 and exhibit a worse prognosis, such as shorter treatment-free time period. Thus, resistance vs. susceptibility to DPP2-inhibiton induced apoptosis can be employed as a novel prognostic factor in CLL.

ADP-ribosyl Cyclase↗
PubMed2006

Prognostic importance of soluble CD23 in B-cell chronic lymphocytic leukemia.

Soluble CD23 (sCD23) was proposed as a marker of disease activity and as an important prognostic parameter in B-cell chronic lymphocytic leukemia (B-CLL). In this study, prognostic significance of sCD23 in B-CLL was examined according to its temporal relationship with the known clinical parameters of the disease, CD38 and ZAP-70. Serum sCD23 levels of 36 B-CLL patients, followed up in our clinic between 1999 and 2005, and 15 healthy subjects were measured with enzyme-linked immunosorbent assay. The mean serum sCD23 level of the B-CLL patients (210.72 +/- 193.67 and 6-600 U/ml) was significantly higher than the control group (18.20 +/- 14.30 and 6-50 U/ml). Seventy-eight percent of the B-CLL patients with lymphocyte doubling time (LDT) <12 months and 24% of patients with LDT >12 months had high sCD23 levels (P = 0.008). Meanwhile, 81% of the patients with diffuse bone marrow infiltration and 33% of patients with nondiffuse infiltration had high levels of serum sCD23 (P = 0.029). A significant difference was found between B-CLL patients with Binet stages A and C (P = 0.009). Peripheral blood flow cytometry of the patients revealed a significant CD38 expression in patients with high serum sCD23 levels (P = 0.002). Similarly, an increased bone marrow zeta-chain associated protein kinase-70 (ZAP-70) expression was seen in patients with high serum sCD23 levels (P = 0.009, correlation co-efficient was 0.714). Cumulative and the progression free survivals of the patients with low serum sCD23 levels were 60.1 +/- 5.7 months [95% confidence interval (CI); 49.0-71.2] and 51.1 +/- 6.6 months (95% CI; 38.0-64.1), respectively. However, they were 43.8 +/- 6.5 months (95% CI; 31.0-56.6) and 26.5 +/- 6.4 months (95% CI; 14.0-39.1) in patients with high levels. Serum sCD23 is increased in B-CLL patients and can be used in the clinical follow-up of the disease in prediction of the tumor mass and prognosis.

ADP-ribosyl Cyclase 1↗
PubMed2006

Bacterial flagellin inhibits T cell receptor-mediated activation of T cells by inducing suppressor of cytokine signalling-1 (SOCS-1).

Flagellin, the structural component of bacterial flagella, is secreted by pathogenic and commensal bacteria, and is recognized by Toll-like receptor (TLR) 5. Flagellin is a common bacterial antigen present on most motile bacteria and is speculated to contribute to the activation of CD4+ T cells in the intestine. However, molecular mechanisms by which flagellin regulate T cell activation remains to be determined. Using Jurkat T cells or human primary T cell, we showed that flagellin stimulation induced tyrosine phosphorylation of TLR5 and activation of both mitogen-activated protein kinases and nuclear factor kappaB. In addition, stimulation by flagellin did not induce nuclear factor of activated T cells (NFAT) activation, while stimulation via the T cell receptor (TCR) leads to activation of NFAT. However, TCR-mediated NFAT activation and tyrosine phosphorylation of zeta-associated protein 70 (Zap-70) were inhibited in cells pre-stimulated by flagellin. Furthermore, flagellin stimulation induced suppressor of cytokine signalling-1 (SOCS-1), which formed a complex with Zap-70 after stimulation via TCR, and inhibition of SOCS-1 expression by SOCS-1-specific small interfering RNA reinstated TCR-mediated activation of NFAT in cells pre-stimulated with flagellin. These results collectively indicate that bacterial flagellin inhibits TCR-mediated activation of T cells by inducing SOCS-1.

Blotting, Western↗
PubMed1998

The Syk family of protein tyrosine kinases in T-cell activation and development.

The processes of T-cell development and activation employ similar immature and mature receptors as well as similar signal transduction pathways to achieve different outcomes. Many signaling molecules are shared between the receptor signaling pathways, including two families of cytoplasmic protein tyrosine kinases, the Src family and the Syk family. The two Syk family members expressed in T cells, Syk and ZAP-70, are structurally similar but are expressed at different times during thymic development and during T-cell activation. These two kinases, although they share many physical features, differ in terms of biochemical activity and regulation. We discuss the overlapping and distinct characteristics of Syk and ZAP-70 in T-cell signaling and the potential biological importance of their differences.

Amino Acid Sequence↗
PubMed1994

Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases.

The T cell antigen receptor (TCR) initiates signals by interacting with cytoplasmic protein tyrosine kinases (PTKs) through a 17-residue sequence motif [called the antigen recognition activation motif (ARAM)] that is contained in the TCR zeta and CD3 chains. TCR stimulation induces the tyrosine phosphorylation of several cellular substrates, including the ARAMs. Lck kinase activity is required for phosphorylation of two conserved tyrosine residues in an ARAM. This phosphorylation leads to the recruitment of a second cytoplasmic PTK, ZAP-70, through both of the ZAP-70 Src homology 2 domains and its phosphorylation. Thus, TCR signal transduction is initiated by the sequential interaction of two PTKs with TCR ARAMs.

Amino Acid Sequence↗
PubMed1997

Activation of the T-cell receptor signaling pathway by Nef from an aggressive strain of simian immunodeficiency virus.

The Nef from a highly virulent strain of simian immunodeficiency virus (SIV), SIVpbj14, and a Nef from the traditional strain SIVmac239 bearing the mutation from RQ to YE (YE-Nef) both induce an acute lethal disease in monkeys. The YE mutation and its surrounding sequence resemble the immunoreceptor tyrosine-based activation motif (ITAM), which is present in the cytoplasmic tail of T- and B-cell antigen receptors and mediates signaling during lymphocyte activation. We show here that the ITAM from YE-Nef performs the same function. First, not only does YE-Nef increase the activity of the transcription factor NFAT, which is one of the downstream targets of T-cell activation, but the ITAM from the YE-Nef by itself also activates NFAT. Second, the ITAM from YE-Nef is phosphorylated on tyrosine residues by Lck and associates with ZAP-70, a T-cell-specific tyrosine kinase. The phosphorylation of both conserved tyrosine residues on the ITAM is required for the recruitment of ZAP-70. Finally, Lck is required for the activation of NFAT by YE-Nef. These results demonstrate that YE-Nef contains a functional ITAM and elucidate the molecular mechanisms underlying the pathogenesis of SIVpbj14.

Amino Acid Sequence↗
PubMed2005

A new direction for gene therapy: intrathymic T cell-specific lentiviral gene transfer.

Reports of neoplasia related to insertional activation of protooncogenes by retroviral vectors have raised serious safety concerns in the field of gene therapy. Modification of current approaches is urgently required to minimize the deleterious consequences of insertional mutagenesis. In this issue of the JCI, Adjali and colleagues report on their treatment of SCID mice lacking the 70-kDa protein tyrosine kinase, ZAP-70, with direct intrathymic injection of a ZAP-70-expressing T cell-specific lentiviral vector, which resulted in T cell reconstitution. Using lentiviral vectors and in situ gene transfer may represent a safer approach than using retroviral vectors for ex vivo gene transfer into HSCs, avoiding 3 factors potentially linked to leukemogenesis, namely HSC targets, ex vivo transduction and expansion, and standard Moloney leukemia virus-based retroviral vectors.

Animals↗
PubMed2004

Stromal cell-derived factor-1alpha/CXCL12-induced chemotaxis of T cells involves activation of the RasGAP-associated docking protein p62Dok-1.

Events mediating stromal cell-derived factor-1 (SDF-1alpha/CXCL12) chemotaxis of lymphocytes are not completely known. We evaluated intracellular signaling through RasGAP-associated protein p62Dok-1 (downstream of tyrosine kinase [Dok-1]) and associated proteins. SDF-1alpha/CXCL12 stimulated Dok-1 tyrosine phosphorylation and association with RasGAP, adaptor protein p46Nck, and Crk-L in Jurkat T cells. The phosphorylation of Dok-1 was blocked by pretreatment of cells with the src kinase inhibitor PP2. Src kinase family member Lck was implicated. SDF-1alpha/CXCL12 did not phosphorylate Dok-1 in J.CaM1.6 cells, a Jurkat derivative not expressing Lck, but did phosphorylate Dok-1 in J.CaM1.6 cells expressing Lck. SDF-1alpha/CXCL12 induced the tyrosine phosphorylation of Pyk2 and the association of Pyk2 with zeta chain-associated protein-70 kilodaltons (Zap-70) and Vav. SDF-1alpha/CXCL12 enhanced the association of RasGAP with Pyk2. CXCR4-expressing NIH3T3 and Baf3 cells transfected with full-length Dok-1 cDNA were suppressed in their responses to SDF-1alpha/CXCL12-induced chemotaxis; mitogen-activated protein (MAP) kinase activity was also decreased. Chemotaxis to SDF-1/CXCL12 was significantly enhanced in Dok-1(-/-) CD4+ and CD8+ splenic T cells. These results implicate Dok-1, Nck, Crk-L, and Src kinases-especially Lck, Pyk2, Zap-70, Vav, and Ras-GAP-in intracellular signaling by SDF-1alpha/CXCL12, and they suggest that Dok-1 plays an important role in SDF-1alpha/CXCL12-induced chemotaxis in T cells.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Anaplastic large cell lymphomas lack the expression of T-cell receptor molecules or molecules of proximal T-cell receptor signaling.

Anaplastic large cell lymphoma (ALCL) designates a heterogeneous group of CD30(+) (systemic or primary cutaneous) peripheral T-cell lymphomas (PTCLs). A subgroup of systemic ALCL is transformed by anaplastic lymphoma kinase (ALK). We compared 24 ALK(+), 15 ALK(-) systemic, and 7 cutaneous ALCLs with 29 nonanaplastic PTCLs in terms of T-cell receptor (TCR) rearrangements, expression of TCRs and TCR-associated molecules (CD3, ZAP-70 [zeta-associated protein 70]). Despite their frequent clonal rearrangement for TCRbeta, only 2 (4%) of 47 ALCLs expressed TCRbeta protein, whereas TCRs were detected on 27 of 29 nonanaplastic PTCLs. Moreover, both TCRbeta(+) ALCLs lacked CD3 and ZAP-70 (ie, molecules indispensable for the transduction of cognate TCR signals). Defective expression of TCRs is a common characteristic of all types of ALCL, which may contribute to the dysregulation of intracellular signaling pathways controlling T-cell activation and survival. This molecular hallmark of ALCL is analogous to defective immunoglobulin expression distinguishing Hodgkin lymphoma from other B-cell lymphomas.

Anaplastic Lymphoma Kinase↗
PubMed2005

Complement regulatory protein Crry/p65-mediated signaling in T lymphocytes: role of its cytoplasmic domain and partitioning into lipid rafts.

Crry/p65 is a type I glycoprotein, which protects mouse T cells from complement attack. We have previously shown that complement receptor I-related protein Crry/p65 (Crry) ligation has a costimulatory effect on mouse CD4+ T cell activation. Here, we have examined the mechanisms responsible for Crry costimulation, addressing the question of whether Crry potentiates signal transduction starting at the T cell receptor (TCR)/CD3 complex or promotes distinct costimulatory signals. We show that Crry increases early TCR-dependent activation signals, including p56lck-, zeta-associated protein-70 (ZAP-70), Vav-1, Akt, and extracellular signal-regulated kinase (ERK) phosphorylation but also costimulation-dependent mitogen-activated protein kinases (MAPK), such as the stress-activated c-Jun N-terminal kinase (JNK). It is intriguing that Crry costimulus enhanced p38 MAPK activation in T helper cell type 1 (Th1) but not in Th2 cells. A fraction of Crry is found consistently in the detergent-insoluble membrane fraction of Th1 or Th2 cells or CD4+ lymphoblasts. Crry costimulation induced clustering of lipid rafts, increasing their content in Crry, CD3epsilon, and p59-60 forms of p56lck, and caused actin polymerization close to the site of activation in Th2 cells. Such events were inhibited by wortmannin, suggesting a role for phosphatidylinositol-3 kinase in these effects. The Crry cytoplasmic domain was required for JNK activation and interleukin-4 secretion but not for the presence of Crry in rafts or activation of p56lck, ZAP-70, Akt, Vav-1, or ERK. This suggests that Crry costimulation involves two different but not mutually exclusive signal transduction modules. The dual function of Crry as a complement regulatory protein and as a T cell costimulator illustrates the importance of complement regulatory proteins as links between innate and adaptive immunity.

Animals↗
PubMed1998

T cell activation deficiency associated with an aberrant pattern of protein tyrosine phosphorylation after CD3 perturbation in Down's syndrome.

Children affected by Down's syndrome (DS) have an increased susceptibility to viral or bacterial infections and leukemia, associated with several abnormalities of the immune system. We investigated whether the T cell defect was qualitative in nature and associated with abnormalities of the early events occurring during cell activation. The proliferative response of lymphocytes from DS individuals after CD3 cross-linking was clearly depressed, as already reported. In contrast, phorbol ester and ionomycin were able to induce cell cycle progression in DS, suggesting a defect in the early stages of the signal transduction through a T cell receptor/CD3 (TCR/CD3) complex upstream of protein kinase C activation. The functional impairment in DS was not related either to a decrease of circulating mature-type CD3+ cells, which express high levels of surface of CD3 molecules, or to a decrease of the CD4+ subpopulation. The analysis of phosphotyrosine-containing proteins after the cross-linking of CD3 molecules in DS lymphocytes revealed a partial signaling, characterized by increased phosphorylation of proteins of 42-44 kD, comparable to that observed in control subjects, but not of proteins of 70 and 21 kD. Moreover, although the "anti-anergic" gamma element of IL-2, IL-4, IL-7, and IL-15 receptors was normally tyrosine-phosphorylated during cell activation, the CD3 zeta-associated protein kinase (ZAP-70) was not. Our results indicate that in DS there is a T cell activation defect, characterized by partial signal transduction through a TCR/CD3 complex, and associated with a selective failure of ZAP-70 tyrosine phosphorylation.

Adolescent↗
PubMed2000

The inhibitory function of CTLA-4 does not require its tyrosine phosphorylation.

CTLA-4 is a negative regulator of T cell responses. Sequence analysis of this molecule reveals the presence of two cytoplasmic tyrosine residues at positions 165 and 182 that are potential Src homology (SH)-2 domain binding sites. The role of phosphorylation of these residues in CTLA-4-mediated signaling is unknown. Here, we show that sole TCR ligation induces zeta-associated protein (ZAP)-70-dependent tyrosine phosphorylation of CTLA-4 that is important for cell surface retention of this molecule. However, CTLA-4 tyrosine phosphorylation is not required for down-regulation of T cell activation following CD3-CTLA-4 coengagement. Specifically, inhibition of extracellular signal-regulated kinase (ERK) activation and of IL-2 production by CTLA-4-mediated signaling occurs in T cells expressing mutant CTLA-4 molecules lacking the cytoplasmic tyrosine residues, and in lck-deficient or ZAP-70-deficient T cells. Therefore, CTLA-4 function involves interplay between two different levels of regulation: phosphotyrosine-dependent cell surface retention and phosphotyrosine-independent association with signaling molecules.

Abatacept↗