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Results for “CD3 Complex”

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PubMed1989

Murine anti-CD3 monoclonal antibody induces potent cytolytic activity in both T and NK cell populations.

Antibodies specific for the CD3 complex have the capacity to both stimulate and inhibit a variety of T cell functions. We show here that a monoclonal antibody to the epsilon chain of CD3 can induce efficient non-MHC-restricted cytolytic activity in murine lymphocytes with peak activity occurring after 48 hr of incubation. In a panel of targets, the anti-CD3-activated effectors lysed tumor cells but not normal lymphoblasts. Cytolysis was not dependent on the presence of the antibody in the cytolytic assay. Moderate to high cytolytic activity was elicited from lymph nodes, spleen, and thymus by anti-CD3 treatment in vitro, whereas only low activity was apparent in bone marrow. The precursors of anti-CD3-activated cells consisted largely of mature T cells, although a smaller component of immature T cells was also involved. Thus, separation of thymocytes based on adhesion to peanut agglutinin revealed that both positive (immature) and negative (mature) fractions could be activated, while cytotoxic pretreatment of spleen cells with an antibody (J11d) to immature T cells before anti-CD3 activation significantly decreased the resulting cytotoxicity. The majority of precursors in spleen were Thy 1+ and CD8+ and/or AGM1+. Antibody depletion studies showed that the effector cells have both a T and a NK component consisting of Thy 1+, CD5+, CD8+, CD4-, and AGM1- cells and Thy 1-, CD5-, CD8-, CD4-, and AGM1+ cells, respectively. The production of significant amounts of IL-2 and TNF in culture following anti-CD3 treatment, along with the synergistic effect of exogenously added IL-2, suggests that one or both of the effector cell types could be induced by lymphokines. The intraperitoneal administration of the anti-CD3 antibody induces cytolytic activity in vivo. Therefore, the direct activation of cytolysis by anti-CD3 antibody and the additional effects, both direct and synergistic, of lymphokines produced by the activated lymphocytes could conceivably provide a potent anti-tumor therapy.

Animals↗

PubMed1993

Programmed cell death of T lymphocytes during acute viral infection: a mechanism for virus-induced immune deficiency.

Acute viral infections induce immune deficiencies, as shown by unresponsiveness to mitogens and unrelated antigens. T lymphocytes isolated from mice acutely infected with lymphocytic choriomeningitis virus (LCMV) were found in this study to undergo activation-induced apoptosis upon signalling through the T-cell receptor (TcR)-CD3 complex. Kinetic studies demonstrated that this sensitivity to apoptosis directly correlated with the induction of immune deficiency, as measured by impaired proliferation in response to anti-CD3 antibody or to concanavalin A. Cell cycling in interleukin-2 (IL-2) alone stimulated proliferation of LCMV-induced T cells without inducing apoptosis, but preculturing of T cells from acutely infected mice in IL-2 accelerated apoptosis upon subsequent TcR-CD3 cross-linking. T lymphocytes isolated from mice after the acute infection were less responsive to IL-2, but those T cells, presumably memory T cells, responding to IL-2 were primed in each case to die a rapid apoptotic death upon TcR-CD3 cross-linking. These results indicate that virus infection-induced unresponsiveness to T-cell mitogens is due to apoptosis of the activated lymphocytes and suggest that the sensitization of memory cells by IL-2 induced during infection will cause them to die upon antigen recognition, thereby impairing specific responses to nonviral antigens.

Animals↗

PubMed1989

Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures.

The receptors found on most T lymphocytes bind to antigen presented on major histocompatibility complex proteins and consist of dimers of alpha- and beta-polypeptides associated with the invariant CD3 complex. A fully competent immune system requires a diverse array of T-cell antigen receptors (TCRs) with different specificities. This diversity is generated by rearrangement of TCR alpha- and beta-chain gene segments within the thymus where the receptors are first expressed. Any cells carrying self-reactive receptors must be eliminated, suppressed or inactivated so that destructive autoimmunity is avoided. Recently, compelling evidence has shown that one process involved in producing such self-tolerance is clonal deletion of autoreactive cells within the thymus by an as-yet-undefined mechanism. Here we show that engaging the CD3/TCR complex of immature mouse thymocytes with anti-CD3 antibodies produces DNA degradation and cell death through the endogenous pathway of apoptosis. Activation of this process in immature T cells by the binding of the TCR to self-antigens may therefore be the mechanism which produces clonal deletion and consequently self-tolerance.

Animals↗

PubMed1995

Signalling events in the anergy induction of T helper 1 cells.

T cells can interact productively with altered peptide ligands (APLs) resulting in different phenotypic outcomes. Stimulation of T helper 1 cells with an APL on live antigen-presenting cells results in the induction of anergy. We investigated the intracellular signalling events involved in generating this anergy by comparing protein tyrosine phosphorylation patterns after stimulation with the anergy-inducing APL or the immunogenic peptide. Stimulation by an APL resulted in a unique pattern of T cell receptor (TCR) phospho-zeta species, which was not observed with any dose of immunogenic peptide. This altered phospho-zeta pattern had a profound functional significance, in that the tyrosine kinase ZAP-70 was not activated. Thus, anergy can be induced by changing the constellation of intracellular signalling events in a T cell. These findings demonstrate that the TCR-CD3 complex can engage selective intracellular biochemical signalling pathways as a direct consequence of the nature of the ligand recognized and the initial phosphotyrosine pattern of the TCR-CD3 proteins. This then leads to different phenotypes.

Clonal Anergy↗

PubMed2003

Perforin-dependent killing of tumor cells by Vgamma1Vdelta1-bearing T-cells.

The T-cell subset expressing Vdelta2 paired primarily with Vgamma2 comprises a majority of gammadelta T-cells in human adult peripheral blood and expands significantly during a variety of infectious diseases. In contrast, the other subset of gammadelta T-cells that express Vdelta1 is rare among circulating T-cells and its function is poorly understood. Here, we show that a Vgamma1Vdelta1(+) T-cell line, 3-D, established from human peripheral blood by immortalization with Herpesvirus saimiri was able to specifically recognize tumor cells, such as K562 cells, and release cytotoxic granules containing perforin for target cell killing. Some tumor cells, including Daudi cells that are known to be susceptible to killing by Vdelta2(+) T-cells, were resistant to 3-D killing, implicating distinct pathways for tumor cell control by Vdelta1(+) and Vdelta2(+) T-cells. The 3-D T-cell receptor (TCR):CD3 complex reconstituted in TCR-deficient Jurkat cells was capable of transmitting signals, evidenced by activation of the interleukin 2 (IL-2) gene following ligation with anti-CD3 antibody, yet the TCR-reconstituted cells failed to produce IL-2 in response to the target cells. Thus, these results raise the possibility that some Vgamma1Vdelta1(+) T-cells could potentially be stimulated and lyse tumor cells via ligation of TCR/CD3-unassociated molecules.

Amino Acid Sequence↗

PubMed2000

Involvement of CD2 and CD3 in galectin-1 induced signaling in human Jurkat T-cells.

Galectin-1 (gal-1) a member of the mammalian beta-galactoside-binding proteins recognizes preferentially Galbeta1-4GlcNAc sequences of oligosaccharides associated with several cell surface glycoconjugates. In the present work, gal-1 has been identified to be a ligand for the CD3-complex as well as for CD2 as detected by affinity chromatography of Jurkat T-cell lysates on gal-1 agarose and by binding of the biotinylated lectin to CD3 and CD2 immunoprecipitates on blots. In CD45(+)Jurkat E6.1 cells, the lectin stimulates a sustained increase in the intracytoplasmic calcium concentration ([Ca(2+)](i)) consisting of both the release of calcium from intracellular stores and the calcium influx from the extracellular space. This effect of gal-1 on [Ca(2+)](i)is completely inhibited by lactose at 10 mM and was absent in CD45(-)Jurkat J45.01 cells. Preincubation of Jurkat E6.1 cells with cholera toxin or with the protein tyrosine kinase inhibitor herbimycin A reduced the gal-1 induced calcium response whereas the increase in [Ca(2+)](i)stimulated by CD2 or CD3 monoclonal antibodies (mAbs) was completely inhibited. Depolarization of E6.1 cells in a high-potassium buffer, a standard method to activate voltage-operated calcium channels, was without effect on [Ca(2+)](i). Membrane depolarization with gramicidin or by a high-potassium buffer was without effects on the lectin-mediated calcium release from intracellular stores but inhibited the gal-1 induced receptor-operated calcium influx. In Jurkat E6.1 cells the lectin stimulates the transient generation of inositol-1,4,5-trisphosphate and the tyrosine phosphorylation of phospholipase Cgamma1. The results suggest that the ligation of CD2 and CD3 by gal-1 induces early events in T-cell activation comparable with that elicited by CD2 or CD3 mAbs.

Antibodies, Monoclonal↗

PubMed1993

Lysis of malignant B cells from patients with B-chronic lymphocytic leukemia by autologous T cells activated with CD3 x CD19 bispecific antibodies in combination with bivalent CD28 antibodies.

Bispecific antibodies (bi-MABs) can be used to target T cells to autologous tumor cells. It has been shown that the activation of resting human T cells requires two independent signals, namely the cross-linking of the T-cell receptor (TCR)-CD3 complex together with the CD28 homodimer. In the present study, we demonstrate the activation of T cells from patients with chronic lymphocytic leukemia (CLL) using bi-MABs against the CD3 and CD19 antigens (CD3 x CD19) in combination with monospecific, bivalent antibodies against the CD28 antigen. Mononuclear cells from patients with CLL were cultured with the bi-MAB CD3 x CD19 and monospecific CD28 antibodies. The CD3 x CD19 bi-MABs were isolated by the hybridoma-hybridoma fusion technique and purified by hydrophobic interaction chromatography. T-Cell activation as demonstrated by increased proliferation, upregulation of T-cell activation markers (CD25, CD38), and cytotoxicity against autologous CLL cells and allogeneic B cells was shown in seven of eight CLL specimens. The stimulation with CD3 x CD19 bi-MABs with CD28 antibodies preferentially induced proliferation of CD4+ T cells. The effective dose of purified antibodies required for optimal T-cell activation was 100 ng/mL in vitro, which suggests that this antibody combination may be useful for immunotherapy of patients with B-CLL.

Adult↗

PubMed1993

Defective calcium-dependent signal transduction in T lymphocytes of ataxia-telangiectasia.

T-cell functions of two patients with ataxia-telangiectasia were investigated. Patients with ataxia-telangiectasia had reduced percentages of circulating CD3+ cells and CD4+ cells, although neither patient had a reduced percentage of circulating CD8+ cells. The proliferative responses and interleukin-2 production of peripheral blood mononuclear cells to T-cell mitogens were reduced in the patients. The intracellular calcium concentration in T cells or CD4+ cells from both patients was only slightly increased after phytohaemagglutinin stimulation. Moreover, the concentration after OKT3 stimulation was not or only slightly increased in T cells or CD4+ cells from both patients. Our results suggest that the functional defect of T cells is caused by defective Ca(2+)-dependent signal transduction through the CD3 complex of the surface in T cells of ataxia-telangiectasia.

Adolescent↗

PubMed1989

Characterization of the IL-2-receptor on rheumatoid arthritis synovial fluid T cells.

We studied the hypoproliferative response of synovial fluid (SF) T cells in rheumatoid arthritis (RA) using a mitogenic monoclonal antibody (MoAb) specific for the T-cell antigen receptor-associated CD3 complex. RASF T cells are defective in their proliferative response and in the induction of the Tac (p55) component of the IL-2-receptor (IL-2-R) when stimulated with anti-CD3 monoclonal antibody (MoAb). However, fresh RASF T cells bear demonstrable IL-2-R in cross-linking experiments which are not seen in unstimulated peripheral blood (PB). These receptors are functional since RASF T cells proliferate in response to recombinant IL-2 (rIL-2) better than fresh PB T cells from either normal or RA patients. Scatchard analysis indicates increased (4-fold) numbers of high affinity IL-2-R on (phytohaemagglutinin) PHA-activated RASF T cells as compared with comparably activated RAPB T cells. Phorbol myristate acetate (PMA) induces Tac antigen expression in RASF but does not lead to proliferation. The hyporesponsiveness of RASF T cells does not appear to result from lack of IL-2-R, lack of IL-2-R inducibility, or proliferative potential.

Adult↗

PubMed1989

Temperature requirements and kinetics of T cell signaling. Velocity of triggering correlates with functional effects of anti-CD3 mAb.

Antibody reactive with the CD3 complex on the surface of T lymphocytes can either: inhibit CTL lysis of target cells expressing Ag; or redirect CTL to lyse target cells expressing FcR in the absence of Ag expression. To investigate these phenomena we examined the effect of anti-CD3 mAb on two indicators of CTL activation, the release of esterase and target cell lysis. Esterase release by long term allo-reactive human CTL in response to target cells (JY or HLA transfected K562 cells) was found to be Ag specific and correlate with target cell lysis. Addition of anti-CD3 to either JY targets or K562 cells expressing FcR resulted in a high level of esterase release. Triggering of esterase release was found with both soluble intact and Fab fragment of anti-CD3 in the absence of cells expressing measurable FcR. This apparent FcR-independent triggering of esterase release occurred at 37 degrees C but not at 24 degrees C. In contrast esterase activity was released from CTL at both 24 and 37 degrees C in response to intact target cells, JY or K562 cells plus intact anti-CD3 mAb. Addition of anti-CD3 mAb, at a level capable of blocking target cell lysis by greater than 50%, resulted in an initial velocity of esterase release almost twice that found in response to JY target cells. With a low level of anti-CD3 mAb, able to block JY lysis by approximately 10%, the initial rate of esterase release was much slower than that found in response to target cells. In contrast when FcR+ cells, K562, were added along with a low level of anti-CD3 the initial velocity of esterase release was about twofold more than the velocity of esterase release triggered by soluble anti-CD3 alone. These results indicate that soluble antibody can trigger long term active CTL and the velocity of this triggering correlates with anti-CD3-mediated inhibition as well as redirected lysis.

Antibodies, Monoclonal↗

PubMed1997

Immobilized anti-CD3 mAb induces anergy in murine naive and memory CD4+ T cells in vitro.

The induction of non-responsiveness in resting murine CD4+ T cells was investigated using immobilized anti-CD3 mAb. Incubation of freshly isolated CD4+ T cells with immobilized anti-CD3 mAb led to apoptosis in 40-60% cells. The surviving cells were profoundly non-responsive to subsequent mitogenic stimulation. The non-responsive state was characterized by a lack of IL-2 production and hyper-responsiveness to added IL-2, but was not explained by further activation-induced cell death. The induction of non-responsiveness was not due to modulation of the TCR-CD3 complex, and required partial activation of the T cells in that it was accompanied by an increase in cell size and was inhibited by addition of cyclosporin A. Finally, analysis of anti-CD3-mediated responses in naive and memory CD4+ T cells, separated on the basis of CD44 expression, showed that both naive and memory T cells have similar sensitivity to immobilized anti-CD3 mAb-induced activation, apoptosis and anergy. These results demonstrate that TCR-CD3 engagement on freshly isolated resting CD4+ naive and memory T cells, In the absence of co-stimulation, as achieved by plastic-immobilized anti-CD3 mAb, induces both anergy and cell death.

Animals↗

PubMed2000

Engagement of CD28 modulates CXC chemokine receptor 4 surface expression in both resting and CD3-stimulated CD4+ T cells.

Optimal CD4+ T cell activation requires the cooperation of multiple signaling pathways coupled to the TCR-CD3 complex and to the CD28 costimulatory molecule. In this study, we have investigated the expression of surface CXC chemokine receptor 4 (CXCR4) in enriched populations of CD4+ T PBL, stimulated with anti-CD3 and anti-CD28 mAbs, immobilized on plastic. Anti-CD3 alone induced a progressive down-regulation of surface CXCR4, accompanied by a significant decline in the entry of the HXB2 T cell line-tropic (X4-tropic) HIV-1 clone in CD4+ T cells. Of note, this effect was strictly dependent on the presence in culture of CD14+ monocytes. On the other hand, anti-CD28 alone induced a small but reproducible increase in the expression of surface CXCR4 as well as in the entry of HXB2 HIV-1 clone in resting CD4+ T cells. When the two mAbs were used in combination, anti-CD28 potently synergized with anti-CD3 in inducing the expression of CD69 activation marker and stimulating the proliferation of CD4+ T cells. On the other hand, anti-CD28 counteracted the CXCR4 down-modulation induced by anti-CD3. The latter effect was particularly evident when anti-CD28 was associated to suboptimal concentrations of anti-CD3. Because CXCR4 is the major coreceptor for the highly cytopathic X4-tropic HIV-1 strains, which preferentially replicate in proliferating CD4+ T cells, the ability of anti-CD28 to up-regulate the surface expression of CXCR4 in both resting and activated CD4+ T cells provides one relevant mechanism for the progression of HIV-1 disease.

Adult↗

PubMed1995

Phosphatidylinositol hydrolysis in freshly isolated human T lymphocytes.

Antigen receptor-mediated activation of T and B lymphocytes results in activation of phospholipase C-gamma isozymes with subsequent hydrolysis of membrane inositol phospholipids. As a method of screening autoimmune or immunodeficient patients for early receptor signaling defects, we have developed a rapid technique for studying phosphatidylinositol (PI) hydrolysis in cultured cells and fresh clinical specimens resulting from surface receptor crosslinking. Using staphylococcal alpha-toxin, we permeabilized freshly isolated, purified human T lymphocytes to facilitate incorporation of [3H]myoinositol into membrane phospholipids. Aggregation of surface antigen receptors (TCR-CD3 complex and CD28 on T cells) with specific antibodies produced extensive ATP and Mg(2+)-dependent hydrolysis of the membrane inositol phospholipids as measured by release of water soluble inositol phosphates. Anti-human CD3 antibody produced 18.5 +/- 1.6 net % PI hydrolysis and anti-human CD28 antibody produced 4.6 +/- 0.2 net % PI hydrolysis. Simultaneous anti CD3/CD28 crosslinking produced 30.8 +/- 1.2 net % PI hydrolysis, an increase over either stimulus alone (p = 0.0013 two tailed t test). Isotype matched control antibodies produced 11.6 +/- 0.4% PI hydrolysis. The tyrosine phosphatase inhibitor orthovanadate (Na3VO4) was used as a positive control because it induces maximal protein tyrosine kinase-dependent PI hydrolysis in permeabilized cells. Na3VO4 consistently induced hydrolysis of > 50% of the membrane inositol phospholipid pool. These data indicate that costimulation of T cells with antibodies to CD3 and CD28 is synergistic and reinforces the importance of CD28 as an accessory T cell stimulus. This easy technique allows quick evaluation of the integrity of the early signaling cascade in lymphocytes as a screen for autoimmune and immunodeficiency diseases.

CD28 Antigens↗

PubMed1988

Molecular cloning of the zeta chain of the T cell antigen receptor.

The T cell antigen receptor is a multi-subunit receptor complex present on the surface of all mature and many developing T cells. It consists of clonotypic heterodimers noncovalently linked to five invariant chains that are encoded by four genes and referred to as the CD3 complex. The CD3 gamma, delta, and epsilon chains have been molecularly characterized. In this report the molecular cloning of a complementary DNA encoding the zeta chain of the murine T cell antigen receptor is described. The predicted protein sequence of the zeta chain suggests a structure distinct from those of any of the previously described receptor subunits.

Amino Acid Sequence↗

PubMed1997

Signals transduced through the CD4 molecule interfere with TCR/CD3-mediated ras activation leading to T cell anergy/apoptosis.

It has been previously demonstrated that the occupancy of CD4 molecules by the HIV-1 envelope glycoprotein gp120 results in marked inhibition of T cell receptor-CD3 complex (TCR/CD3) activation-induced IL-2 secretion. To elucidate the mechanism of inhibitory effects of gp160 on T cell signaling, we have investigated the intracellular biochemical events and biological output in response to anti-CD3 mAb activation of purified peripheral blood CD4+ T cells from healthy donors with and without prior exposure to HIV-1 gp160. Pretreatment with gp160 resulted in marked inhibition of tyrosine phosphorylation of p59(fyn), PLC-gamma1, ras activation, and TNF-alpha secretion in anti-CD3 mAb activated CD4+ T cells, and a subset of CD4+ cells underwent activation-induced cell death. The data presented here provide insight into the mechanism by which the interaction of HIV-1 envelope glycoproteins with CD4 molecules may alter TCR/CD3-activation-induced signal transduction resulting in anergy and apoptosis with consequent functional deficiency of CD4+ T cells.

Apoptosis↗

PubMed1998

Cytotoxic T lymphocyte antigen 4 is induced in the thymus upon in vivo activation and its blockade prevents anti-CD3-mediated depletion of thymocytes.

The development of a normal T cell repertoire in the thymus is dependent on the interplay between signals mediating cell survival (positive selection) and cell death (negative selection or death by neglect). Although the CD28 costimulatory molecule has been implicated in this process, it has been difficult to establish a role for the other major costimulatory molecule, cytotoxic T lymphocyte antigen (CTLA)-4. Here we report that in vivo stimulation through the T cell receptor (TCR)-CD3 complex induces expression of CTLA-4 in thymocytes and leads to the association of CTLA-4 with the SH2 domain-containing phosphatase (SHP)-2 tyrosine phosphatase. Moreover, intrathymic CTLA-4 blockade dramatically inhibits anti-CD3-mediated depletion of CD4+CD8+ double positive immature thymocytes. Similarly, anti-CD3-mediated depletion of CD4+CD8+ double positive cells in fetal thymic organ cultures could also be inhibited by anti-CTLA-4 antibodies. Thus, our data provide evidence for a role of CTLA-4 in thymic selection and suggest a novel mechanism contributing to the regulation of TCR-mediated selection of T cell repertoires.

Abatacept↗

PubMed2000

Comparison of Fas- versus perforin-mediated pathways of cytotoxicity in TCR- and Thy-1-activated murine T cells.

T cell-mediated cytotoxicity can be triggered by cross-linking of TCR or Thy-1 surface proteins. While the TCR-triggered signaling initiates both perforin- and Fas ligand (FasL)-Fas-mediated mechanisms of cytotoxicity, it was not clear which mechanism was utilized by Thy-1-triggered signals and which pathway of cytotoxicity was triggered at low levels of antigen expression. It is shown that glycophosphatidylinositol-linked surface glycoprotein Thy-1 preferentially activates FasL-Fas- but not perforin-mediated cytotoxicity. This is explained by the lesser intensity of Thy-1-mediated signaling in T cells. The data suggest that Thy-1-triggered Fas-mediated cytotoxicity is completely dependent on cross-talk between Thy-1 and TCR signals since mutations in TCR-CD3 complex molecules or inhibition of tyrosine kinases or calcineurin abolished or strongly inhibited Thy-1-triggered FasL-Fas-mediated cytotoxicity. Lower concentrations of antigenic peptide or levels of cross-linking with anti-TCR-CD3 mAb are required to trigger Fas-mediated than perforin-mediated cytotoxicity by different cytotoxic T lymphocyte (CTL) lines and clones, and it is shown that cross-linking of Thy-1 is much less efficient in triggering accumulation of second messengers (intracellular Ca(2+)) than cross-linking of TCR on CTL. Taken together, these data reflect the possibility of differential activation of FasL and/or perforin pathways of cytotoxicity depending on the nature of activating stimuli and surface receptor.

Animals↗

PubMed1997

Major histocompatibility complex class I molecules modulate activation threshold and early signaling of T cell antigen receptor-gamma/delta stimulated by nonpeptidic ligands.

Killer cell inhibitory receptors and CD94-NKG2-A/B heterodimers are major histocompatibility complex class I-specific inhibitory receptors expressed by natural killer cells, T cell antigen receptor (TCR)-gamma/delta cells, and a subset of TCR-alpha/beta cells. We studied the functional interaction between TCR-gamma/delta and CD94, this inhibitory receptor being expressed on the majority of gamma/delta T cells. When engaged by human histocompatibility leukocyte antigen class I molecules, CD94 downmodulates activation of human TCR-gamma/delta by phosphorylated ligands. CD94-mediated inhibition is more effective at low than at high doses of TCR ligand, which may focus T cell responses towards antigen-presenting cells presenting high amounts of antigen. CD94 engagement has major effects on TCR signaling cascade. It facilitates recruitment of SHP-1 phosphatase to TCR-CD3 complex and affects phosphorylation of Lck and ZAP-70 kinase, but not of CD3 zeta chain upon TCR triggering. These events may cause abortion of proximal TCR-mediated signaling and set a higher TCR activation threshold.

Antigens, CD↗