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PubMed1991

Surface expression of the beta T cell receptor (TCR) chain in the absence of other TCR or CD3 proteins on immature T cells.

T cell receptor (TCR) beta genes are rearranged prior to TCR alpha genes. A productively rearranged TCR beta gene suppresses further V beta gene rearrangement. Here we show that in beta TCR transgenic mice the TCR beta-chain can be expressed on the surface of immature CD4-8- thymocytes, but not on mature T cells, in the absence of any other known TCR chain and proteins of the CD3 complex. Analysis by NEPHGE and SDS-PAGE showed that at least some beta TCR exists on the surface as a large disulfide-linked complex with unknown acidic molecules. The introduction of the beta TCR gene into scid mice resulted in the expression of the beta TCR on the cell surface of thymocytes and induced the expression of CD4 and CD8 co-receptors as well as transcription of the alpha TCR locus.

Animals↗

PubMed1994

Humanization of the murine anti-human CD3 monoclonal antibody OKT3.

OKT3 is a murine monoclonal antibody which recognizes an epitope on the epsilon-subunit within the human CD3 complex. OKT3 possesses potent immunosuppressive properties in vivo and has been proven effective in the treatment of renal, heart and liver allograft rejection. Despite its efficacy, significant problems remain associated with OKT3 therapy, i.e. T-cell activation and the anti-murine antibody response. To address the problem of the anti-murine antibody response we have constructed humanized versions of OKT3. One of the humanized derivatives, gOKT3-7 incorporating the OKT3 complementarity determining regions plus a small number of alterations to the human framework, has an affinity of 1.4 x 10(9) M-1 compared with 1.2 x 10(9) M-1 for the murine OKT3. A humanized antibody (gOKT3-1) incorporating only the CDRs from OKT3 was found to be functionally inactive, confirming the requirement for nonCDR substitutions. gOKT3-7 retains the ability of mOKT3 to induce T cell proliferation in vitro and appears to be a good candidate for further development for in vivo therapy.

Amino Acid Sequence↗

PubMed1997

Requirements for differentiation of an immature CD4+8+ T-cell line.

The CD3 epsilon and zeta chains of the TCR have been shown to possess independent signaling capabilities. Studies with chimeric molecules containing the cytoplasmic domains of either zeta or epsilon have suggested that these two structurally distinct members of the TCR-CD3 complex are able to function autonomously and have redundant features in the context of TCR-signal transduction in mature T cells. Expression of a chimeric human IL-2-receptor-zeta-chain molecule in the CD4+8+ T-cell line, DPK, has enabled us to directly analyze responses initiated by the zeta-chain-signaling module alone within the context of immature T-cell differentiation. In this paper, we show that antibody crosslinking of the chimeric zeta chain delivers only a limited activation signal as measured by Ca[2+] flux, induction of low-level CD5 expression, and minimal differentiation as assessed by loss of cell-surface CD8 expression. TCR-induced activation through antibody crosslinking of the endogenous CD3 epsilon receptor in the absence of costimulation was also relatively inefficient in initiating activation and differentiation. However, co-crosslinking of the CD4 coreceptor with CD3 resulted in a synergistic response, where as there was little effect of co-crosslinking of CD4 and the zeta-chain chimera. Striking differences were also observed in the substrate pattern of tyrosine phosphorylation, as well as lymphokine secretion following triggering through the intact TCR versus the zeta chain alone. These results indicate that although the zeta-chain may possess some signaling capacities similar to that of the intact TCR, it appears to have limited function as an autonomous subunit in initiating CD4+8+ T-cell differentiation.

Animals↗

PubMed1994

A common factor regulates both Th1- and Th2-specific cytokine gene expression.

Murine T helper cell clones are classified into two distinct subsets, T helper 1 (Th1) and T helper 2 (Th2), on the basis of cytokine secretion patterns. Th1 clones produce interleukin-2 (IL-2), tumor necrosis factor-beta (TNF-beta) and interferon-gamma (IFN-gamma), while Th2 clones produce IL-4, IL-5, IL-6 and IL-10. These subsets differentially promote delayed-type hypersensitivity or antibody responses, respectively. The nuclear factor NF-AT is induced in Th1 clones stimulated through the T cell receptor-CD3 complex, and is required for IL-2 gene induction. The NF-AT complex consists of two components: NF-ATp, which pre-exists in the cytosol and whose appearance in the nucleus is induced by an increase of intracellular calcium, and a nuclear AP-1 component whose induction is dependent upon activation of protein kinase C (PKC). Here we report that the induction of the Th2-specific IL-4 gene in an activated Th2 clone involves an NF-AT complex that consists only of NF-ATp, and not the AP-1 component. On the basis of binding experiments we show that this 'AP-1-less' NF-AT complex is specific for the IL-4 promoter and does not reflect the inability of activated Th2 cells to induce the AP-1 component. We propose that NF-ATp is a common regulatory factor for both Th1 and Th2 cytokine genes, and that the involvement of PKC-dependent factors, such as AP-1, may help determine Th1-/Th2-specific patterns of gene expression.

Animals↗

PubMed1989

Delineation of human thymocytes with or without functional potential by CD1-specific antibodies.

Hematopoietic precursors lacking T cell antigen receptors (TCR-CD3-) and CD4 and CD8 surface markers (i.e. double-negative thymocytes) give rise to functionally mature T lymphocytes. Yet their major progeny are immunologically unresponsive thymocytes in spite of having acquired TCR-CD3 and CD4-CD8. Because only mature thymocytes migrate to peripheral lymphoid organs and most thymocytes die in situ, the knowledge of the events associated with functional maturation in the double-negative thymocyte progeny is a fundamental question in T cell development. We reasoned that a clue to trace the fate of early human thymocytes may perhaps come from the study of the developmental acquisition of CD1 antigen, currently used to define better the functionally inert CD4+8+ (double-positive) stage and absent in mature, medullary thymocytes and peripheral T cells. By using antibodies specific for CD1 (HTA 1/T6) we show here that a large fraction of double-negative thymocytes also express CD1. CD1+3-, CD1+3+, CD1-3+, and CD1-3- subsets all exist. The CD1+3- subset generates CD1+3-4-8+ precursors of CD1+ double-positive cells. A large portion of the CD1+3+ subset bears TCR gamma delta-CD3 complexes. The CD1- subsets are responsive in assays of function, in which they can be stimulated to use the interleukin 2 pathway of proliferation and to mediate cytotoxicity. In contrast, all CD1+ thymocytes behave as functionally inert cells. Thus, the CD1 surface marker delineates human thymocyte precursors and their products which lack, or possess, functional potential in vitro, on both alpha beta and gamma delta lineages.

Antibodies, Monoclonal↗

PubMed1992

Effect of methylxanthine derivatives on T cell activation.

In a Phase I-II trial examining the effect of prophylactic administration of pentoxifylline (PTX) on bone marrow transplant-associated morbidity, there was an apparent reduction in the incidence and severity of acute graft-versus-host disease. To determine if PTX might be directly immunosuppressive, its effects on T cell activation and proliferation were examined. PTX and several cogeners were found to directly suppress T cell proliferation in response to phytohemagglutinin, to allogeneic cells in a mixed leukocyte reaction, and to cross-linking the CD3 complex. The effects were dose-related and associated with suppression of secretion of tumor necrosis factor-alpha (TNF alpha). However, the inhibition of proliferation was not solely due to this effect since adding excess recombinant TNF alpha did not restore the proliferative response. These data suggest that PTX may be clinically useful in suppressing allogeneic reactions in bone marrow transplantation.

Antigens, Differentiation, T-Lymphocyte↗

PubMed2004

T cell receptor induced intracellular redistribution of type I protein kinase A.

The productive activation of CD4(+) T lymphocytes, leading to proliferation and cytokine secretion, requires precise temporal regulation of intracellular cyclic AMP concentrations. The major effector molecule activated by cyclic AMP in mammalian cells is the cyclic AMP-dependent protein kinase A (PKA). The type I PKA isozyme mediates the inhibitory effects of cyclic AMP on T-cell activation. Using laser scanning confocal microscopy, we demonstrated that the regulation of PKA type I activity involves spatial redistribution of PKA type I molecules following T-cell receptor (TCR) stimulation. In resting T cells, PKA type I was located in membrane proximal regions and distributed equally across the cell. Shortly after antigen engagement, T cells and antigen-presenting cells formed an area of intense contact, known as the immunological synapse. TCR concentrated at the synapse, whereas PKA type I molecules redistributed to the opposite cell pole within 10 min after T-cell stimulation. Type I PKA redistribution was solely dependent on TCR signalling, because we observed the same temporal and spatial distribution after antibody-mediated cross-linking of the TCR-associated CD3 complex. Segregation of TCR and PKA type I molecules was maintained for at least 20 min. Thirty minutes after stimulation, PKA type I partially colocalized with the TCR. After 60 min, PKA type I distribution again approached the resting state. Considering that initial TCR signals lead to increases in intracellular cyclic AMP, PKA type I molecules may be targeted towards localized cyclic AMP accumulations or transported away from these areas, depending on the requirements of the cellular response.

Animals↗

PubMed1999

Generation of antigen-specific cytotoxic T lymphocytes and regulation of cytokine production takes place in the absence of CD3zeta.

The TCR-associated protein CD3zeta plays a major role in regulating the state of responsiveness to peptide-MHC complexes on the surface of antigen-presenting cells. In this paper the requirement of CD3zeta in the generation of cytotoxic T cells was compared with its requirement in cytokine gene activation in two mutant mice: ZKO mice with a disrupted CD3zeta gene and ZTG mice in which a truncated CD3zeta segment was expressed as a transgene on the ZKO background. Upon infection of ZTG mice with lymphocytic choriomeningitis virus (LCMV), antigen-specific cytotoxic T lymphocyte (CTL) responses were detected, identical to responses in wild-type mice. In addition, antigen-specific CTL responses to allogeneic class I and class II MHC in ZTG animals were indistinguishable from those in wild-type animals. However, CTL responses to the same major antigens were not detectable in ZKO mice. We conclude that the signal transduction pathways leading to CTL development and cytokine production can be triggered through TCR in the absence of functional CD3zeta, provided the remainder of the TCR-CD3 complex is expressed at high levels on the cell surface. Surprisingly, IFN-gamma production in response to LCMV followed the same kinetics in ZKO, ZTG and wild-type mice. However, in vitro studies showed that cytokine production in general was abnormally regulated in T lymphocytes from ZKO mice, in contrast to ZTG T cells. Taken together, these studies support the hypothesis that development of CTL can take place in the absence of functional CD3zeta. However, CTL development requires stronger TCR-initiated signal transduction events than induction of cytokine genes.

Abatacept↗

PubMed1989

Rearrangement and expression of T-cell receptor delta genes in T-cell acute lymphoblastic leukemias.

We have analyzed T-cell receptor delta (TcR-delta) gene rearrangement and transcription in appropriately phenotyped mononuclear cells derived from 12 patients with T-cell acute lymphoblastic leukemia (T-ALL). The T-ALL cells were also analyzed for rearrangement and transcription of the T-cell receptor(TcR)-beta and gamma genes as well as for the presence of TcR-alpha gene transcripts. Four T-ALLs expressed TcR-gamma delta at the cell surface, while three expressed TcR-alpha beta. The other five T-ALLs did not express a TcR-CD3 complex on their cell membrane. The TcR-gamma delta + T-ALL had rearranged both TcR-delta gene alleles and contained mature 2.2 and 1.5 kb TcR-delta transcripts. In one case, immature 1.9 and 1.2 kb TcR-delta transcripts were also found. Furthermore they contained mature TcR-gamma mRNA, mature or immature TcR-beta mRNA, but no TcR-alpha mRNA. The three TcR-alpha beta + T-ALLs contained mature alpha and beta transcripts, but lacked TcR-delta transcripts as a result of deletion of both TcR-delta gene alleles. These data are in line with a mutually exclusive expression of TcR-alpha and -delta genes, which may be important to ensure the presence of only one type of TcR per T cell. One of the five CD3- T-ALLs had germline TcR-beta, gamma, and delta genes. The other four CD3- T-ALLs had rearranged their TcR-beta, gamma, and delta genes and contained immature 1.9 and 1.2 kb TcR-delta gene transcripts. Remarkably, one of these T-ALLs also contained TcR-alpha transcripts in addition to the immature TcR-delta transcripts, which was in line with the deletion of one TcR-delta gene allele and rearrangement of the other allele. This suggests that prevention of dual receptor expression may not only be regulated by the presence of germline TcR-alpha genes in TcR-gamma delta + cells or by deletion of both TcR-delta gene alleles in TcR-alpha beta + cells, but also via other regulation mechanisms. Finally, our data indicated that the combinatorial repertoire of the TcR-delta genes is limited, which has also been described for the TcR-gamma genes.

Antigens, Differentiation, T-Lymphocyte↗

PubMed2004

Early events associated to the oral co-administration of type II collagen and chitosan: induction of anti-inflammatory cytokines.

Oral administration of an antigen can result in local and systemic priming or tolerance and the basis of this dichotomy is poorly understood. The intestinal microenvironment, and factors such as nature of the antigen, dose, genetic background, uptake and concentration of the antigen that gain access to the internal milieu via the mucosa influence these active immunologic processes. Chitosan is a biocompatible natural polysaccharide able to promote the transmucosal absorption of peptides and proteins. The aim of our work was to study the effect of the co-administration of type II collagen (CII) and chitosan during the initial contact of the antigen with the immune system. Sixteen hours after feeding we evaluated several molecular events in mucosal and in systemic lymphoid tissues. We determined in Peyer's patches (PP) and spleen cells the number and activation of T cells, the arrival of the antigens, and the cytokine profile. In PP we found a reduction in the cell number without changes in CD3(+) cells. In spleen, instead, we observed an increase in CD3(+) cells as well as the internalization of the CD3 complex. CII:chitosan-fed animals exhibited a reduced secretion of IL-2 with an increase of IL-10 in PP and spleen respectively. In addition, in PP, CII:chitosan-fed rats showed increased levels of mRNA for transforming growth factor-beta, IL-4 and IL-10. Together, our data suggest that the co-administration with chitosan modifies the uptake and/or the distribution of the relevant antigen, and promotes an anti-inflammatory environment early after feeding.

Administration, Oral↗

PubMed2004

Using live FRET imaging to reveal early protein-protein interactions during T cell activation.

The emerging challenge for proteomics in general and lymphocyte biology in particular is to understand protein-protein interactions in the dynamic context of the living cell. Particularly interesting are the molecular dynamics of the T cell receptor-CD3 complex and other immunoreceptors in immune synapses. Fluorescence (or Förster) resonance energy transfer (FRET) is one of the few techniques that are capable of giving dynamic information about the nanometer-range proximity between molecules, as opposed to simply the subcellular co-localization that is provided by fluorescence microscopy. Spectral changes in fluorescence intensity and down modulation of donor lifetime are the basis for rapidly developing approaches to real-time FRET imaging. With two-photon excitation, FRET can now be extended to in vivo imaging.

Animals↗

PubMed2004

Using live FRET imaging to reveal early protein-protein interactions during T cell activation.

Animals↗

PubMed1992

Ligation of VLA-4 on T cells stimulates tyrosine phosphorylation of a 105-kD protein.

The VLA/integrins are a family of heterodimeric adhesion receptors shown to be involved in cell-to-cell and cell-to-extracellular matrix (ECM) interactions. Given recent evidence that VLA molecules can synergize with the CD3/T cell receptor (TCR) pathway to activate T cells, it is important to identify biochemical event(s) generated by these molecules. Here, we report that the engagement of VLA-4 on T cells with specific antibodies or its ligand activates protein-tyrosine kinase (PTK) activity as detected by antiphosphotyrosine immunoblotting. The crosslinking of VLA-beta 1 (CD29) with a specific monoclonal antibody (mAb) (anti-4B4) plus anti-mouse immunoglobulin resulted in the rapid tyrosine phosphorylation of a 105-kD protein (pp105) in the human T cell line H9, as well as in peripheral resting T cells. The increase in tyrosine phosphorylation of pp105 was specifically mediated by VLA-4, since mAbs against alpha 4, but not against other VLA alpha chains, could induce this phosphorylation. In addition, the binding of T cells with the CS1 alternatively spliced segment of fibronectin (the binding site recognized by VLA-4) induced pp105 tyrosine phosphorylation. Crosslinking the CD3 complex or VLA-4 molecules with mAbs demonstrated that each of these molecules stimulated the tyrosine phosphorylation of unique sets of proteins with different kinetics, suggesting that these two receptor systems are coupled to distinct PTKs. Since tyrosine phosphorylation of cellular proteins has been shown to be a crucial biochemical event in cell growth, our findings suggest that the induction of pp105 tyrosine phosphorylation via VLA-4 may play a role in the transduction of activation signals through this molecule.

Antigens, CD↗

PubMed2005

Regulation of lck degradation and refractory state in CD8+ cytotoxic T lymphocytes.

After specific activation, CD8+ cytotoxic T lymphocytes (CTLs) enter a refractory state termed activation-induced nonresponsiveness (AINR) that is characterized by the inability of T cells to respond to a secondary stimulus. Here, we show that T cell receptor triggering results in rapid degradation of the src-family protein kinase lck through a mechanism that is proteasome- and lysosome-independent, sensitive to cysteine protease inhibitors, and distinct from the pathways involved in degradation of ZAP-70 kinase or zeta-chain of the CD3 complex. Pharmacologic blockade of lck degradation, as well as transfection of refractory cells with an lck expression vector, increased responsiveness of CTLs to repeated antigenic challenge. The development or maintenance of AINR was not affected by exogenously added IL-2, whereas IL-15 or IFN-alpha restored both lck expression and responsiveness of preactivated CTLs. Our results suggest that lck degradation plays an important role in the development of AINR in human CTLs and that this condition can be reverted by pharmacologic agents or lymphokines that prevent lck degradation or induce its expression.

CD3 Complex↗

PubMed2004

Up-regulation of IL-4 production by the activated cAMP/cAMP-dependent protein kinase (protein kinase A) pathway in CD3/CD28-stimulated naive T cells.

The signal transduction of the cAMP/cAMP-dependent protein kinase [protein kinase A (PKA)] pathway through multiple receptors is critical for many processes in all cell types. In T cells, the engagement of both the TCR-CD3 complex and the CD28 co-stimulatory molecule also induces cAMP, and subsequently activates PKA. It is believed that elevation of cAMP levels in T cells is inhibitory of IL-2 production and T cell proliferation. However, the function and detailed signal transduction mechanisms of the cAMP/PKA pathway in naive T(h) cells are less well understood. In this study, we show that calcitonin gene-related peptide (CGRP) down-regulates IL-2 and IFN-gamma production and up-regulates IL-4 production to promote T(h)2 differentiation by moderate activation of the cAMP/PKA pathway via the CGRP receptor in the presence of a CD3/CD28 co-stimulation signal. The IL-4 production and transcriptional activation of T(h)2 cytokine mRNAs were also reproduced by the addition of a cAMP analogue, dibutyryl-cAMP, in CD3/CD28-stimulated naive T(h) cells. More interestingly, cAMP/PKA activation in naive T(h) cells stimulated with anti-CD3 plus anti-CD28 mAb is essential for inducing IL-4 production and promoting T(h)2 differentiation; in addition, NF-AT is a downstream effector of the cAMP/PKA signaling pathway. These findings indicate that the cAMP/PKA pathway transduces the critical activation signal to T(h)2 polarization by a CD3/CD28 co-stimulation signal and a PKA activating reagent.

Animals↗

PubMed1992

[The T-lymphocyte antigen receptor].

The precise knowledge of the T-cells antigen receptor (TCR) is of paramount importance; it is the first structure involved in the antigen (allergen) recognition, provided this one is presented in the right conditions; that is in the context of HLA molecules present at the surface of macrophages, after being processed inside. The TCR alpha/beta, present on more than 90% of peripheral T cells, is formed of two glyco-protein chains of similar molecular weight. The cytoplasmic end of the TCR is two short to transmit the message of recognition. The signal is transduced by neighbouring molecules forming the CD3 complex. Other membrane proteins such as CD2, LFA1, reinforce adhesion between immuno-competent cells. The presence or absence of CD4 or CD8 surface antigens, permit to distinguish two T cell subpopulations, namely helper and suppressor/cytotoxic lymphocytes. The TCR gene organization is very similar to that of light and heavy chains of immunoglobulins. Their fortuitous rearrangement explains the very large diversity of the T-cell repertoire. The TCR gamma/delta, although first appeared on the thymic cells, is present on less than 5% of peripheral lymphocytes, where its exact role is still unknown.

Animals↗

PubMed1992

The natural killer cell-like lytic activity expressed by cytolytic T lymphocytes is associated with the expression of a novel function-associated molecule.

Experiments were performed to analyse the natural killer cell (NK)-like cytotoxicity frequently expressed by human antigen-specific cytolytic T lymphocytes (CTL). To this end, several monoclonal antibodies (MoAbs) previously shown to identify a novel function-associated molecule (FAM) involved in human NK function were utilized. Flow cytometry revealed that these MoAbs reacted with the majority of human NK, but only with a subpopulation of CTL isolated from primary mixed lymphocyte cultures. Preincubation of CTL with the MoAbs inhibited the NK-like lysis of K562 targets. Experiments with anti-CD3 MoAb demonstrated that neither the NK-like cytotoxicity of CTL nor the lytic activity of NK were mediated by the CD3 complex. Expression of the novel FAM was found to develop in T-cell cultures at the time that NK-like cytotoxicity was observed. Repeated in vitro antigenic stimulation of CTL was shown to result in loss of NK-like cytotoxicity, as well as loss of the FAM on the CTL surface. Thus, NK-like cytotoxicity displayed by antigen-specific CTL appears to be mediated by a novel FAM that is identical to that structure found on NK.

Adolescent↗

PubMed2004

[Expression of factors inducing apoptosis of peripheral blood lymphocytes in oral cavity cancers].

One of possible immunosuppression mechanisms during cancer disease is apoptotic death of immunology system cells. Factor FAS and xi chain of TCR-CD3 complex take part in induction of apoptosis of lymphocyte which infiltrate neoplasm as well as lymphocytes of peripheral blood (PBL). Expression of the two factors was estimated in PBL of patients with cancer of bottom of oral cavity and granuloma fissuratum (control group). During cancer disease higher level of FAS factor in PBL was observed in comparison to control group. Lymphocytes of peripheral blood in cases of cancer disease shown lower expression of TCR-xi.

Adult↗