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At least 469 records · Page 26Linked to original sources

PubMed1999

Translocation of tyrosine-phosphorylated TCRzeta chain to glycolipid-enriched membrane domains upon T cell activation.

Recent studies point to glycolipid-enriched membrane (GEM) microdomains as the critical sites for TCR-mediated signal transduction. However, whether the TCR complex is localized in the GEM domain is not well-defined. In the present study, we analyzed localization of the TCR-CD3 complex in the GEM domain by isolating the GEM fraction with sucrose density gradient centrifugation. Although 10% of TCRzeta chains was localized in the GEM fraction, most of the TCR complexes were excluded from the GEM before and after T cell activation, and the amount of TCRzeta in the GEM was not increased after activation. However, the tyrosine-phosphorylated form of TCRzeta was strongly concentrated in the GEM fraction upon TCR engagement. A kinetic study revealed that tyrosine phosphorylation of TCRzeta occurred initially in the Triton X-100-soluble membrane fraction followed by the accumulation of phosphorylated TCRzeta in the GEM. Thus, these results indicate that phosphorylated TCRzeta migrates into the GEM domains on T cell activation. We speculate that the GEM microdomains may function as a reservoir of activation signals from triggered TCR.

Animals↗

PubMed1988

Impaired clonal expansion in athymic nude CD8+CD4- T cells.

A comparative study of the phenotype and immune functions of highly purified CD8+CD4- T cells obtained from the spleen and thymus of normal mice and from the spleen of athymic nude mice was conducted. Of seven individual normal and nude mice examined, the range of V beta 8+ cells among CD8+ T cells was a heterogeneous 4.3 to 30.5% for athymic nude mice and a much more uniform spread from 14.7 to 18.5% for normal mice. In six of the seven nude mice examined, the fraction of V beta 8+ cells was below the lower limit of the V beta 8 distribution in normal mice. However, one of the seven nude mice contained nearly twice the percentage of normal V beta 8+ cells. A reduction in the density of V beta 8 as well as CD3 Ag expression was also observed in athymic CD8+CD4- cells although an Ly-6-linked Ag, B4B2 displayed a highly increased expression. Considering the battery of Ag analyzed in entirety, athymic CD8+CD4- T cells were clearly distinct from their "counterpart" CD8+CD4- T cells isolated from either thymus or spleen of normal (euthymic) mice. Anti-CD3-mediated triggering of the TCR:CD3 complex caused extensive clonal proliferation in cultures to which single responding CD8+ T cells had been deposited. Under identical conditions, however, anti-CD3 caused little, if any clonal expansion in CD8+ cells from athymic nude mice. Highly purified athymic CD8+CD4- cells produced readily detectable IL-2R expression and IL-2 synthesis and secretion upon stimulation by anti-CD3 and by Con A. Production of IL-2 by purified athymic CD8+CD4- cells was due to CD8+CD4- cells and not due to a minor population of contaminating CD8- cells as anti-CD8 + C treatment completely abrogated the ability of athymic CD8+CD4- cells to produce IL-2. Despite IL-2 production and IL-2R expression by athymic nude CD8+CD4- T cells in response to anti-CD3 and to Con A, an impaired proliferative response followed.

Animals↗

PubMed1994

Role of the CDR1 region of the TCR beta chain in the binding to purified MHC-peptide complex.

Single alanine substitutions were introduced into the CDR1 region of the beta chain of a Kd-restricted TCR. Mutants and wild-type TCR were attached to the zeta chain of the CD3 complex and expressed at the surface of a rat basophil cell line. Transfectants were tested for the binding of purified soluble Kd-peptide complexes. With this experimental system, accessory molecules are unlikely to play a major role and the contribution of each residue to the interaction can be addressed. Results show that all positions in the CDR1 region are involved in the binding to the Kd-peptide complex but at varying degrees. These effects are discussed in relation to a molecular model of the TCR. Comparison of these results with previous data obtained in a T cell hybridoma system suggests the existence of a threshold in the TCR affinity necessary for mature T cell activation.

Animals↗

PubMed1993

A novel disulfide-linked heterodimer on pre-T cells consists of the T cell receptor beta chain and a 33 kd glycoprotein.

We describe a novel signal-transducing protein complex, which consists of the T cell receptor (TCR) beta chain that is disulfide linked to a 33 kd glycoprotein and noncovalently associated with proteins of the CD3 complex on the surface of the pre-T cell line SCB.29. This 33 kd glycoprotein, provisionally designated gp33, represents neither of the known TCR chains and has escaped previous detection because it labels poorly by surface iodination. This glycoprotein is absent from the surface of mature T cell lines. A TCR beta complex with identical molecular masses before and after reduction can be immunoprecipitated from surface-iodinated large thymocytes of TCR alpha-deficient mice. The novel gp33-TCR beta complex may be entirely or partly responsible for control of early T cell development exerted by the TCR beta protein.

Animals↗

PubMed1992

Bispecific antibody therapy of two murine B-cell lymphomas.

Numerous in vitro studies have shown that T lymphocytes can be targeted towards any target cell by using bispecific antibodies (bsAbs) with specificity of the CD3/TCR complex and a target cell antigen. We have produced bsAbs directed against the membrane expressed idiotype of the murine B cell lymphomas BCLI and 38C13, and murine CD3 complex. The dual specificity of the hybrid-hybridoma produced monoclonal antibodies (MAbs) could be demonstrated by flow cytometry, the induction of T cell proliferation, the induction of IL2 secretion by polyclonal T cells, and redirected lysis of the relevant target cells. Immunotherapy of tumor bearing animals demonstrated that bsAbs could efficiently target T cells towards the tumor cells, that tumor cell--T cell bridging is established in vivo, and that both T cell subsets contribute to tumor regression resulting in long-term survival and cure of the lymphomas.

Animals↗

PubMed1994

Partial T cell signaling: altered phospho-zeta and lack of zap70 recruitment in APL-induced T cell anergy.

Studies of T cell responses to altered peptide ligands (APLs) have provided functional evidence that a T cell receptor (TCR) can interpret subtle changes in its ligand, resulting in different phenotypic outcomes. One dramatic effect of APL stimulation with live antigen-presenting cells (APCs) is the induction of energy as opposed to proliferation. We investigated the intracellular signaling events involved in generating this unresponsiveness by comparing protein-tyrosine phosphorylation patterns after stimulation with anergy-inducing APL or the immunogenic peptide. In resting T cell clones, presentation with APL/live APC stimulated a unique pattern of TCR phospho-zeta species and a subsequent lack of association with zap70. This demonstrates that the TCR-CD3 complex can engage selective intracellular biochemical signaling pathways as a direct consequence of the nature of the ligand recognized and the initial phosphotyrosine pattern of the TCR-CD3 proteins, leading to different phenotypes.

Amino Acid Sequence↗

PubMed1996

CD8 enhances formation of stable T-cell receptor/MHC class I molecule complexes.

T-cell antigen receptors (TCR) generally interact with moderate affinity with the complex formed by major histocompatibility complex (MHC) molecules and foreign peptides. MHC/TCR recognition is followed by the generation of a signal to the T cell through a monomorphic multicomponent system that includes the CD3 complex and accessory molecules such as CD4 and CD8. The interaction between the extracellular domains of MHC and TCR molecules, and the interaction of MHC and CD4/CD8 molecules, have been considered to occur independently of one another. We report here that the affinity of CD8 dimers for MHC class I molecules is independent of haplotype and peptide content, and that the affinity of the TCR for its specific ligand is enhanced through a reduced 'off' rate in the presence of either CD8alpha alpha homo- or CD8alpha beta heterodimers. Moreover, CD8 seems to help recognition of the specific MHC-peptide complex either by guiding an energetically favourable docking of TCR onto MHC, or by inducing conformational changes in the MHC complex that can augment the TCR/MHC-peptide interaction. CD8 should therefore be considered as an active participant in the T-cell recognition complex, rather than simply as an accessory molecule.

Animals↗

PubMed2006

Specificity on a knife-edge: the alphabeta T cell receptor.

The interaction between the alphabeta T cell receptor (TCR) and the peptide bound to the major histocompatibility complex class I molecule (pMHC-I) constitutes a central interaction in adaptive immunity. How these receptors interact with such low affinity while maintaining exquisite specificity for peptide antigen and host MHC (MHC-I restriction) remains a challenge to be explained by structural immunologists. Moreover, how this extracellular interaction is transmitted as an intracellular signal via the CD3 complex remains unresolved. Nevertheless, several structures of TCRs, non-liganded and ligated to a defined pMHC-I, combined with detailed biophysical analyses, have provided insight of the structural basis of MHC-I restriction. In addition, structures of isolated CD3 components have enabled T cell signalling mechanisms to be postulated. Recent findings in this area, which include seven distinct TCR/pMHC-I complexes, have fundamental implications in adaptive immunity as well as therapeutic applications to modulate the adaptive immune response.

Animals↗

PubMed1995

Interactions between the tyrosine kinases p56lck, p59fyn and p50csk in CD4 signaling in T cells.

Interaction of the CD4 co-receptor with major histocompatibility complex (MHC) class II molecules during antigen presentation results in enhancement of antigen receptor signaling. The synergism between the two receptors is believed to result from the juxtaposition of the CD4-associated tyrosine kinase p56lck with the cytoplasmic domains of CD3 complex components. Here, we report that cross-linking of CD4 on the surface of Jurkat cells using monoclonal antibodies results in activation of the CD3-associated kinase p59fyn. Co-cross-linking of CD4 and CD3 results in synergistic activation of p59fyn. The p59fyn kinase is also hyperactive in a Jurkat cell line stably transfected with a constitutively active p56lck mutant, indicating that p56lck mediates CD4 activation of p59fyn. In support of this hypothesis, expression of a dominant inhibitory mutant of p59fyn blocks CD4 signals involved in gene activation. In addition, the p59fyn dominant inhibitor mutant blocks gene-activating signals induced by expression of a constitutively active mutant of p56lck. Overexpression of the regulatory kinase p50csk, which attenuates TcR signaling by inactivation of p59fyn, inhibits signaling from the constitutively active form of p56lck. Taken together, these data suggest that CD4/p56lck enhancement of TcR signaling is, at least in part, mediated by activation of p59fyn, and may be regulated by p50csk.

CD4 Antigens↗

PubMed1990

T lymphocytes can mediate lysis of autologous melanoma cells by multiple mechanisms: evidence with a single T cell clone.

The specificity analysis of a CD3+, WT31+, CD8+ cytotoxic T lymphocyte (CTL) clone (CTL 49), isolated from peripheral blood lymphocytes of a melanoma patient (no. 665) after mixed lymphocyte culture with an HLA-A2+ allogeneic lymphoblastoid cell line (VSKB-LCL), revealed that CTL 49 could lyse, in addition to HLA-A2+ lines, autologous HLA-A2- melanoma (Me665/2) and K562 targets. Killing of VSKB-LCL, but not of Me665/2, could be inhibited by anti-CD3 and by anti-HLA-A2 antibodies or by modulation of the CD3 complex. Cold-target competition studies showed that K562, but not VSKB-LCL, could compete with Me665/2 for lysis by CTL 49. However, unlike K562, Me665/2 could be lysed by CTL 49 in a Ca2(+)-independent fashion in 4 h and 18 h assays. CTL 49 expressed mRNA specific for tumor necrosis factor (TNF alpha) and, to a lesser extent, for lymphotoxin (TNF beta). Exposure of the clone to anti-CD3 antibodies induced the expression of interferon(IFN)-gamma-specific mRNA. Antibodies to TNF alpha, TNF beta and IFN reduced the lysis of Me665/2, but not of K562, by CTL 49 in 18-h cytotoxic assays. Antibodies to TNF alpha and to IFN gamma almost completely inhibited the lysis seen on Me665/2 (but not on K562), in 96-h assays, by supernatants isolated from VSKB-LCL- or anti-CD3-stimulated CTL 49 cells. Taken together, these data indicate that major-histocompatibility-complex-independent lysis of autologous tumor cells and of natural killer reference targets by the same alloreactive T cell clone are activities related at the level of target recognition but distinct at the level of the lytic hit. Thus, efficient lysis of autologous tumor cells results from a complex mechanism based upon direct effector-target interaction as well as on cytokine-mediated cytolytic effects.

Calcium↗

PubMed1986

Antibody binding to CD5 (Tp67) and Tp44 T cell surface molecules: effects on cyclic nucleotides, cytoplasmic free calcium, and cAMP-mediated suppression.

T cells can be activated to proliferate by antibodies to the T cell antigen receptor or the molecularly associated CD3 complex if monocytes are present. We have shown previously that monoclonal antibodies to the human T cell differentiation antigens CD5 (Tp67) and Tp44 each augment and prolong proliferative responses of anti-CD3-activated T cells, even in the absence of monocytes. Here we show that the functional and biochemical mechanisms of CD5 and Tp44 signal transmission are distinct. T cell proliferation is suppressed by agents that increase the concentration of intracellular cAMP. We found that antibody binding to the Tp44 surface molecule overcomes this suppression, whereas antibody binding to CD5 does not, indicating that ligand-Tp44 interaction changes T cell sensitivity to cAMP-mediated growth inhibition. The ability of anti-CD3, anti-Tp44, and anti-CD5 monoclonal antibodies to directly alter cyclic nucleotide levels in the Jurkat T cell line was examined. Anti-CD3 alone caused a rapid four- to sixfold increase in cAMP levels, but did not affect cGMP levels. However, anti-Tp44 and anti-CD5 each caused a rapid three- to fourfold increase in cGMP levels without affecting cAMP levels. In other experiments, cytoplasmic free calcium levels were measured in resting T cells after CD5 or Tp44 stimulation by using the dye indo-1 and flow cytometry. This sensitive method showed that anti-CD5 alone caused an increase in cytoplasmic calcium free levels within 3 min of antibody addition, whereas anti-Tp44 had no effect. Finally, anti-Tp44 and IL 1 each augmented proliferation of phorbol ester-stimulated lymphocytes, whereas anti-CD5 did not. The effects of IL 1 and Tp44 could be further distinguished in that the effect of anti-Tp44 was resistant to inhibition by dBcAMP whereas IL 1 was not. These data suggest that the receptor function of both Tp44 and CD5 involves changes in cyclic nucleotides levels, and that the mechanism by which anti-Tp44 and anti-CD5 antibodies affect T cell proliferative responses may be related to their selective effects on cGMP levels and cytoplasmic calcium concentrations.

Antibodies, Monoclonal↗

PubMed1998

Neuroendocrine control of the thymus.

Thymocytes undergo a complex process of differentiation, largely dependent on interactions with the thymic microenvironment, a tridimensional cellular network formed by epithelial cells, macrophages, dendritic cells, and fibroblasts. One key cellular interaction involves the TCR-CD3 complex expressed by thymocytes with MHC-peptide complexes present on microenvironmental cells. Additionally, thymic epithelial cells (TEC) interact with thymocytes via soluble polypeptides such as thymic hormones and interleukins, as well as through extracellular matrix (ECM) ligands and receptors. Such types of heterotypic interactions are under neuroendocrine control. For example, thymic endocrine function, represented by thymulin production, is up-regulated, both in vivo and in vitro, by thyroid and pituitary hormones, including prolactin and growth hormone. We also showed that these peptides enhance the expression of ECM ligands and receptors, as well as the degree of TEC-thymocyte adhesion. In addition, we studied the thymic nurse cell complex, used herein as an in vitro model for ECM-mediated intrathymic T-cell migration. We observed that T-cell migration is also hormonally regulated as ascertained by the thymocyte entrance into and exit from these lymphoepithelial complexes. Taken together these data clearly illustrate the concept that neuroendocrine circuits exert a pleiotropic control on thymus physiology. Lastly, the intrathymic production of classic hormones such as prolactin and growth hormone suggests that, in addition to endocrine circuits, paracrine and autocrine interactions mediated by these peptides and their respective receptors may exist in the thymus, thus influencing both lymphoid and microenvironmental compartments of the organ.

Animals↗

PubMed1989

Activation of protein kinase C via the T-cell receptor complex potentiates cyclic AMP responses in T-cells.

We have recently shown that activation of protein kinase C by tumour promoting phorbolesters, such as 4 beta-phorbol-12,13-dibutyrate, stimulates adenosine-induced accumulation of cAMP in Jurkat cells, a human T-leukaemia line. Activating the CD3 complex associated with the T-cell receptor by means of the monoclonal antibody OKT3 caused a concentration-dependent accumulation of inositol phosphates and an increase in the phosphorylation of an endogenous protein kinase C substrate. OKT3 also mimicked the previously reported effects of protein kinase C since it potentiated the cAMP stimulation by either an adenosine analogue, NECA, or cholera toxin. Thus, our results indicate that stimulation of a receptor activating phospholipase C and protein kinase C can secondarily enhance the action of agonists that act on adenylate cyclase-coupled receptors.

Adenosine↗

PubMedDate not supplied

A T-cell receptor gamma/CD3 complex found on cloned functional lymphocytes.

Cloned blood lymphocytes that do not express the alpha- and beta-chains of the T-cell receptor show MHC-unrestricted cytotoxicity. These cells carry the gamma-protein, disulphide-linked either to another molecule or to itself, and associated with the CD3 complex. These observations may help to solve the mystery posed by the discovery of the gamma gene.

Antigens, Differentiation, T-Lymphocyte↗

PubMed1988

Triggering of co-mitogenic signals in T cell proliferation by anti-LFA-1 (CD18, CD11a), LFA-3, and CD7 monoclonal antibodies.

Proliferative T cell responses were elicited in a comitogenic assay when purified mAb against CD 18, CD11a, LFA-3, and CD7 were immobilized onto solid plastic surfaces together with submitogenic doses of mAb against the CD3 complex. The proliferative response was associated to the production of IL-2 and to the expression of IL-2R. We explored the possibility that a second signal provided by either PMA or a Ca2+ ionofore could replace the anti-CD3 mAb in the comitogenic assay. Interestingly, our data clearly indicate that PMA but not the ionofore was capable of mediating the co-mitogenic effect in conjunction with solid-bound mAb (CDw18, CD11a, LFA-3, and CD7). We also demonstrate that the mAb (anti-CD4 and anti-CD2) which have been previously described as co-mitogenic in combination with anti-CD3 are capable of eliciting this activating signal in the presence of PMA. These data indicate that mAb to certain cell surface differentiation Ag that in soluble form inhibit T cell function such as LFA-1, LFA-3, and CD2 can under appropriate conditions induce co-mitogenic signals on T cells. Our results support the hypothesis that several cell surface differentiation Ag may participate in conjunction with the T3-Ti complex in the transmembrane signal transduction leading to T cell activation.

Antibodies, Monoclonal↗

PubMed1990

Severe combined immunodeficiency in man with an absence of immunoglobulin gene rearrangements but normal T cell receptor assembly.

An autosomal recessive type of severe combined immunodeficiency disease (SCID) was characterized by an absence of immunoglobulins (Ig) in the serum and of Ig+ lymphocytes in bone barrow (BM) and peripheral blood. In the BM CD10+/terminal deoxynucleotidyl transferase-positive lymphocytes were identified. Epstein-Barr virus-transformed B lymphoblastoid cell lines (BLCL) obtained from BM and peripheral blood did not synthesize Ig. The Ig heavy and light chain gene complexes in the BLCL had retained the germ-line configuration. Mature T cells were present but their numbers in peripheral blood were decreased. T lymphoblastoid cells derived from peripheral blood expressed normal T cell receptor (TcR) CD3 complexes and manifested various genomic TcR rearrangements. It was concluded that this type of SCID entailed a complete arrest of B lymphocyte differentiation in an early stage prior to Ig rearrangements and a quantitative defect of T lymphocytes which nevertheless allowed development of mature T cells. Repeated failures of BM transplantation and the striking absence of Ig assembly suggested that this SCID defect resides in the BM microenvironment.

Antigens, CD↗

PubMed1997

The tumour associated cell surface antigen A6H is costimulatory for human CD4+ but not CD8+ T cells.

The A6H monoclonal antibody (mAb) recognizes a 120,000-140,000 MW antigen that is expressed at similar densities on 85-90% of human CD4+ and CD8+ T cells and on renal cell carcinomas. The binding of the A6H mAb induced a costimulatory signal in anti-CD3 activated T cells. In the present report, we show that A6H costimulated cell proliferation and cytokine production in purified CD4+ T cells. Unexpectedly, the CD8+ T-cell subpopulation failed to respond. CD4+ T cells costimulated with the A6H mAb upregulated CD80, CD86, CD71, interleukin-2 (IL-2)R alpha, IL-2R beta and IL-2R gamma, while no corresponding up-regulation of these cell surface molecules was seen in CD8+ T cells. In order to investigate the nature of the A6H mAb costimulus at the transcriptional level we have examined induction of the transcription factors OCT-1, AP-1 and NF-kappa B which are known to be transcriptional regulators of several cytokine and cytokine receptor genes, including the IL-2 and IL-2R genes. Co-ligation of the A6H antigen and the CD3 complex induced expression of the transcription factor AP-1 in CD4+ T cells, whereas no increase in NF-kappa B and octamer-binding (Oct) proteins was seen compared to T cells stimulated with anti-CD3 alone. Furthermore, no induction of AP-1 was seen in A6H costimulated CD8+ T cells. These results suggests that both proximal steps in CD8+ T-cell activation as well as the later phases are unresponsive to A6H ligation. Molecular differences of the A6H molecule or distinct regulation of the A6H transduced AP-1 activation pathway may exist in CD4+ and CD8+ T cell subpopulations.

Antibodies, Monoclonal↗

PubMed1989

A possible basis for major histocompatibility complex-restricted T-cell recognition.

Four distinct T-cell antigen-receptor gene loci have now been identified and partly characterized: alpha, beta, gamma and delta. All of these loci can rearrange in an immunoglobulin-like fashion and express polypeptides that contribute to either alpha:beta or gamma:delta T-cell receptor-CD3 complexes. Surprisingly, the T-cell receptor (TCR) delta coding regions are located entirely, or almost entirely, within the TCR alpha locus and share at least some of the V region gene segments, thus at least partly linking the two different types of receptor heterodimers. Analysis of potential T-cell receptor diversity, particularly that of the delta chain, indicates a striking concentration of somatic polymorphism in the V-J junctional region of the two heterodimers, four to six orders of magnitude higher than similar calculations for immunoglobulin light- and heavy-chain combinations. In contrast, the number of possible V region combinations in T-cell receptors is one hundredth to one thousandth that of immunoglobulins. TCR alpha: beta heterodimers are known to recognize many possible fragments of antigens embedded in the peptide-binding clefts of a relatively small number of major histocompatibility complex (MHC) molecules. Thus it is attractive to speculate that the V-J junctional portions of both types of T-cell receptor contact peptide antigens, whereas the remaining diversity regions contact the MHC. This contention is supported by molecular modelling studies and has interesting implications for the evolution of antigen-receptor genes.

Antibody Diversity↗