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At least 757 records · Page 42Linked to original sources
PubMed1999

Antigen-induced TCR-CD3 down-modulation does not require CD3delta or CD3gamma cytoplasmic domains, necessary in response to anti-CD3 antibody.

We studied cytotoxic T lymphocyte (CTL) clones expressing cytoplasmic domain-deleted CD3delta and CD3gamma chains. These cells retained efficient antigen-specific cytolysis. Because the cytoplasmic domains of native CD3delta and CD3gamma chains contain a dileucine-based and a tyrosine-based motif thought to be important for receptor endocytosis, we compared TCR-CD3 down-modulation on the CTL clones expressing or not these domains. We found that antigen-induced TCR-CD3 down-modulation was not dependent on either the CD3delta or CD3gamma cytoplasmic domains. This contrasts with phorbol ester- and anti-CD3 mAb (soluble or plastic-coated)-induced TCR-CD3 down-modulation, that are respectively dependent on CD3gamma and on either CD3delta or CD3gamma cytoplasmic domains, suggesting that differences may exist between the mechanisms of TCR-CD3 down-modulation in response to the three stimuli. TCR-CD3 down-modulation in response to antigen was demonstrated by confocal microscopy to be associated with TCRbeta chain internalization, whether CD3delta and CD3gamma were native or truncated. Inhibition by the protein tyrosine kinase inhibitor PP1 of TCR-CD3 down-modulation in response to antigen was also similar whether CD3delta and CD3gamma cytoplasmic domains were present or not. These properties of receptor down-modulation are discussed with respect to the requirements for TCR engagement on antigen-presenting cells.

Animals↗
PubMed1989

T cell activation induced by anti-CD3 antibodies requires prolonged stimulation of protein kinase C.

Accessory cell-depleted T cells required the presence of a protein kinase C (PKC) stimulating phorbol ester, such as phorbol 12,13-dibutyrate (PDB), to be activated by soluble antibodies to the CD3 molecular complex. To determine the duration of PDB costimulation necessary to induce a proliferative response, highly purified T cells were pulsed with anti-CD3, incubated with PDB for limited periods of time, and then washed and recultured in the absence of PDB. T cells stimulated with anti-CD3 and PDB for 2 hr were unable to proliferate unless IL-2 or PDB was added to the second culture. With more prolonged exposure to PDB (4-18 hr), anti-CD3-pulsed cells exhibited an increased capacity to proliferate in the absence of additional PDB. Proliferation could be augmented by exogenous IL-2, but remained submaximal. Optimal DNA synthetic responses required the presence of PDB throughout the entire culture. Despite this, costimulation with anti-CD3 and PDB induced a significant number of cells to express IL-2 receptors and enter the cell cycle after 18 hr of costimulation with PDB. Moreover, T cells costimulated by anti-CD3 and PDB produced IL-2 within 4 hr. However, T cells that were stimulated with anti-CD3 and PDB for 4 hr, washed, and recultured rapidly lost the ability to continue to produce IL-2, which reflected a decrease in the content of mRNA encoding IL-2. This loss of IL-2 production was prevented by reculturing the cells with PDB. These studies therefore indicate that after initial T cell activation by anti-CD3, continued stimulation of PKC is necessary for ongoing IL-2 production. These results suggest a model of T cell activation in which sustained stimulation of PKC after cell cycle entry is required to maintain growth factor production and continued proliferation.

Adult↗
PubMedDate not supplied

Regulation of T-cell receptor gamma-chain RNA expression in murine Thy-1+ dendritic epidermal cells.

The epidermis of normal mice contains two distinct populations of dendritic cells derived from the bone marrow, Ia+ Langerhans cells and Ia- cells that express the Thy-1 alloantigen. The Thy-1-bearing dendritic epidermal cells (Thy-1+ dEC) have a surface phenotype similar to that of very early T-lineage cells, produce IL-2-like growth factors and exhibit cytotoxicity which is not restricted by the major histocompatibility complex (MHC). The relationship of Thy-1+ dEC to the T-cell lineage is unclear. Most T lymphocytes bear a receptor for antigen composed of an alpha chain and a beta chain associated with a nonpolymorphic complex termed CD3 (T3). A minor population carries a receptor in which CD3 is associated with a gamma/delta complex. We have analysed clones of Thy-1+ dEC for rearrangement and expression of the genes for the alpha-, beta- and gamma-chains of the T-cell receptor (TCR). They do not express alpha or beta but do carry a gamma/delta complex. Activation of the cells with Con A is associated with a rapid decrease in the steady-state level of gamma-chain RNA. Because Thy-1+ dEC resemble early stage T lymphocytes, down-regulation of TCR expression may reflect a necessary event during T cell differentiation.

Animals↗
PubMed1997

Analysis of T-cell receptor beta of the T-cell clones reactive to the human PDC-E2 163-176 peptide in the context of HLA-DR53 in patients with primary biliary cirrhosis.

T-cell-mediated autoimmune mechanisms are considered to be involved in the pathogenesis of primary biliary cirrhosis (PBC). In the previous study, we identified the immunodominant T-cell epitope on the E2 component of pyruvate dehydrogenase complex (PDC-E2) in patients with PBC who have HLA-DRB4*0101. In this report, we revealed that the frequency of the T cells reactive to the human PDC-E2 163-176 peptide is significantly increased in the peripheral blood of patients with PBC as compared with healthy subjects. We also confirmed that these T cells were all restricted with HLA-DRB4*01 (DR53) by using HLA-DR-transfected L cells. These results together with the evidence that the immunodominant B-cell epitope overlaps with the human T-cell epitope of the PDC-E2 antigen indicate that the T cells reactive to this epitope are closely associated with the pathogenesis of PBC at least in patients who have HLA-DR53. Therefore, we analyzed the T-cell receptor (TCR) Vbeta sequence of the five different T-cell clones and the three T-cell clones derived from three patients with PBC and healthy subjects, respectively, which are reactive to the human PDC-E2 163-176 peptide in the context of HLA-DR53. The Vbeta- and the Jbeta-gene usages were diverse among the T-cell clones (Vbeta11-Jbeta1.4, Vbeta8-Jbeta1.2, Vbeta12-Jbeta2.1, Vbeta10-Jbeta1.5, and Vbeta20-Jbeta2.1) in patients with PBC. By contrast, in the third complementarity determining region (CDR3), G was frequently found and GXG or GXS motif was identified in all T-cell clones. Moreover, RGXG motif was found in three clones generated from two patients. In healthy subjects, the Vbeta- and the Jbeta-gene usages were also diverse, and GXG and RGXG motif were found. These results indicate that the T cells may recognize the ligand (the human PDC-E2 163-176 peptide/HLA-DR53 complex) using the limited motif in the CDR3 region and that the design of CDR3-specific immunotherapy would be possible using these motifs.

Amino Acid Sequence↗
PubMed2005

The immune privilege of the eye: human retinal pigment epithelial cells selectively modulate T-cell activation in vitro.

PURPOSE: To examine the effect of human retinal pigment epithelial (RPE) cells on phytohemagglutinin (PHA) activation of T cells. METHODS: Resting peripheral blood lymphocytes (PBLs) were stimulated with PHA with or without the presence of gamma-irradiated RPE cells. Proliferation and the cell cycle profile were thereafter investigated by 3H-thymidine incorporation and flow cytometric analysis. In addition, the PBLs expression of CD69, major histocompatibility complex (MHC) class I and II, CD3, as well as the IL-2 receptor chains were evaluated by flow cytometry, and the content of IL-2 in cell culture supernatant was measured by ELISA. RESULTS: Human RPE cells were found to suppress PHA-induced proliferation, cyclin A, IL-2R-alpha and -gamma, and CD71 expression and decrease the production of IL-2; but RPE cells do not inhibit the PHA-induced expression of early activation markers CD69, MHC class I and II, and of cyclin D of the PBLs. CONCLUSIONS: These results are the first to indicate that RPE cells impede generation of activated T cells by interfering with the induction of high-affinity IL-2R-alphabetagamma, IL-2 production, and the expression of CD71 and cyclin A.

Antigens, CD↗
PubMed1988

Identification of CD2-/CD3+ T cells in fetal human tissue.

From 1 to 23% of fetal human spleen or thymus cells (from the 20th to 24th week of gestation) were found to display a previously unrecognized CD2-/CD3+ phenotype. IL-2-dependent, long-term clones of CD2-/3+ T cells did not react with a panel of anti-CD2 mAbs and did not form rosettes with sheep erythrocytes. These results show that (a) significant numbers of CD2-/3+ T cells are present in fetal human spleen and/or thymus; and (b) in contrast to the widely accepted view, expression of CD2 is not a prerequisite for the expression of the CD3 molecular complex on human T cells.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1999

[Morphological study of CD3+ dendritic epidermal T cells in human skin and scar].

OBJECTIVE: To investigate the CD3/TCR-bearing T cell in the epidermis and explore the influence of the dendritic epidermal T cells on regeneration and differentiation of epidermal cells. METHODS: The CD3/TCR-bearing T cells in epidermis of human skin and cicatrix were examined by means of histomorphology and immunohistochemistry. RESULTS: It was found that the density of CD3/TCR-bearing T cells in human skin and scar tissue had great dissimilarity. CD3+ dendritic epidermal T cells increased in hyperplastic scar. Such result was not observed in atrophic scar. CONCLUSION: Our findings indicate CD3+ dendritic epidermal T cells regulate the generation and differentiation of epidermal cells. CD3+ dendritic epidermal T cells may play an important role in the maintenance of the morphology of epidermal tissue.

Adult↗
PubMed1986

The structure and function of the T3-Ti molecular complex on human T lymphocytes.

Recent studies using cloned antigen-specific T lymphocytes and monoclonal antibodies directed at their various surface glycoprotein components have led to identification of the human T cell antigen receptor as a surface complex composed of a clonotypic 90-kDa Ti heterodimer and the invariant 20- and 25-kDa T3 molecules. Approximately 30,000-40,000 Ti and T3 molecules exist on the surface of human T lymphocytes. These glycoproteins are acquired and expressed during late thymic ontogeny, thus providing the structural basis for immunologic competence. The Ti alpha and Ti beta subunits bear no precursor-to-product relationship and are encoded by separate germ line V, D, J, and C segments, which rearrange during intrathymic differentiation to form an active gene set. Triggering of the T3-Ti receptor complex induces a rapid increase in free cytoplasmic Ca2+ and gives rise to specific antigen-induced proliferation through an autocrine pathway involving endogenous IL 2 production, release, and subsequent binding to IL 2 receptors.

Amino Acid Sequence↗
PubMedDate not supplied

Serological level of ICAM and ELAM adhesion molecules in allergic vascularitis.

A 24-patient lot with hypersensitivity vasculitis was investigated for serological determinations of ICAM and ELAM adhesion molecules. Determinations were made in attack and in remission. Over two thirds of the cases presented elevated serological levels of ICAM and ELAM in attack, with twofold higher values than normal. In remission, in the absence of clinical signs, ICAM and ELAM values were normal in 19 cases (ICAM) and 22 cases (ELAM). Serological level of ICAM and ELAM was concordant with serological level of IL-2, IL-6, circulating immune complexes and clinical status. The increased values of ICAM and ELAM are due to the expression of these molecules both on the surface of endothelial cells and on immune cells. The adherence of leukocytes on the endothelial cells, by adhesion molecules involvement, followed by their extravasation represents an important event in the vascular lesion pathogeny of the hypersensitivity vasculitis.

Adult↗
PubMed2002

TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex.

We show in this study that human T cells purified from peripheral blood, T cell clones, and Jurkat T cells release microvesicles in the culture medium. These microvesicles have a diameter of 50-100 nm, are delimited by a lipidic bilayer membrane, and bear TCR beta, CD3epsilon, and zeta. This microvesicle production is regulated because it is highly increased upon TCR activation, whereas another mitogenic signal, such as PMA and ionomycin, does not induce any release. T cell-derived microvesicles also contain the tetraspan protein CD63, suggesting that they originate from endocytic compartments. They contain adhesion molecules such as CD2 and LFA-1, MHC class I and class II, and the chemokine receptor CXCR4. These transmembrane proteins are selectively sorted in microvesicles because CD28 and CD45, which are highly expressed at the plasma membrane, are not found. The presence of phosphorylated zeta in these microvesicles suggests that the CD3/TCR found in the microvesicles come from the pool of complexes that have been activated. Proteins of the transduction machinery, tyrosine kinases of the Src family, and c-Cbl are also observed in the T cell-derived microvesicles. Our data demonstrate that T lymphocytes produce, upon TCR triggering, vesicles whose morphology and phenotype are reminiscent of vesicles of endocytic origin produced by many cell types and called exosomes. Although the exact content of T cell-derived exosomes remains to be determined, we suggest that the presence of TCR/CD3 at their surface makes them powerful vehicles to specifically deliver signals to cells bearing the right combination of peptide/MHC complexes.

Apoptosis↗
PubMed1998

Signaling through a CD3 gamma-deficient TCR/CD3 complex in immortalized mature CD4+ and CD8+ T lymphocytes.

The biologic role of each CD3 chain and their relative contribution to the signals transduced through the TCR/CD3 complex and to downstream activation events are still controversial: they may be specialized or redundant. We have immortalized peripheral blood CD4+ and CD8+ T lymphocytes from a human selective CD3 gamma deficiency using Herpesvirus saimiri. The accessibility of the mutant TCR/CD3 complex to different Abs was consistently lower in immortalized CD8+ cells when compared with CD4+ cells, relative to their corresponding CD3 gamma-sufficient controls. Several TCR/CD3-induced downstream activation events, immediate (calcium flux), early (cytotoxicity and induction of surface CD69 or CD40L activation markers or intracellular TNF-alpha) and late (proliferation and secretion of TNF-alpha), were normal in gamma-deficient cells, despite the fact that their TCR/CD3 complexes were significantly less accessible than those of controls. In contrast, the accumulation of intracellular IL-2 or its secretion after CD3 triggering was severely impaired in gamma-deficient cells. The defect was upstream of protein kinase C activation because addition of transmembrane stimuli (PMA plus calcium ionophore) completely restored IL-2 secretion in gamma-deficient cells. These results suggest that the propagation of signals initiated at the TCR itself can result in a modified downstream signaling cascade with distinct functional consequences when gamma is absent. They also provide evidence for the specific participation of the CD3 gamma chain in the induction of certain cytokine genes in both CD4+ and CD8+ human mature T cells. These immortalized mutant cells may prove to be useful in isolating cytosolic signaling pathways emanating from the TCR/CD3 complex.

CD4-Positive T-Lymphocytes↗
PubMed1998

Trichosanthin inhibits T cell activation by interfering with the recruitment of ZAP-70 to CD3 zeta chain.

Plant protein Trichosanthin (Tk) has been shown in our previous experiments to suppress antigenic response of T cells. Here we explored its inhibitory mechanisms on the proliferation of human Jurkat leukemia T cell triggered by anti-CD3 McAb. By examination of tyrosine phosphorylation of cell lysate, we were able to show that Tk could interfere with the PTK-related activity in the TCR/CD3-initiated signal transduction in addition to blocking the phosphorylation of PKC. As shown in our experiment, the expression intensity of ZAP-70, a kind of protein tyrosine kinase, was not changed but its phosphorylation could be inhibited. When physical link between CD3 zeta chain and ZAP-70 was further examined by using coimmunoprecipitation after pluse-treatment of the cell line with Tk, the anti-CD3 McAb-induced recruitment of ZAP-70 to CD3 zeta chain was observed to be blocked in some extent. This may account for, at least in part, how Trichosanthin was able to inhibit the TCR-triggered T cell proliferation.

Antibodies, Monoclonal↗
PubMed1995

Functional assessment of CD2, CD3 and CD28 on the surface of peripheral blood T-cells from infants at low versus high genetic risk for atopy.

Recent studies from several laboratories suggest that the rate of postnatal maturation of T-cell function(s) associated with in vitro activation may be slower in children at high genetic risk for atopy (HR), compared to their normal (low risk; LR) counterparts. The present study compared the in vitro activity of the function-associated surface molecules CD2, CD3 and CD28 in panels of 27 HR and 13 LR infants, with a reference panel of 10 adults, employing assay systems involving T-cell stimulation with MoAbs against these molecules. The response maxima induced by saturating levels of the MoAbs were equivalent in all 3 groups, but T-cells from the HR infants required 10-50 fold higher levels of anti-CD3 stimulation to attain their maximum response, relative to adults (p = 0.02); T-cells from LR infants were also less responsive to anti-CD3 than adults, but these differences were smaller and did not attain statistical significance. It is suggested that these differences are attributable to varying proportions of competent T-memory cells (which respond to low levels of anti-CD3) in PBL from these populations, the postnatal accumulation of which proceeds slowest in the HR group.

Adult↗
PubMed1992

Selective immunosuppression with anti-T cell monoclonal antibodies.

Murine monoclonal antibodies specifically directed at the CD3 molecular complex are widely used in clinical practice. They are potent inhibitors of immune function and may be administered in association to conventional immunosuppressants. The main purpose of this review is to summarize our present knowledge on the CD3 molecule, to discuss the available data on the clinical use of anti-CD3 MoAb (therapeutic effectiveness, mode of action and side effects) and the recent information derived from the use of anti-CD3 MoAb in experimental models that are opening new perspectives in the applications of anti-CD3 and will hopefully lead to the extension of its clinical use to settings different from transplantation.

Animals↗
PubMed1996

Enhancement of CD3-mediated thymocyte apoptosis by the cross-linkage of heat-stable antigen.

Heat-stable antigen (HSA) is a murine differentiating antigen that is expressed on both CD4-CD8- double-negative and CD4+CD8+ double-positive thymocytes but not CD4+ or CD8+ single-positive thymocytes. Effects of anti-HSA monoclonal antibody, R13, on thymocyte apoptosis induced by various stimulations were investigated by a single-cell suspension culture system. Immobilized R13 enhanced the CD3-mediated DNA fragmentation and killing of thymocytes but not the dexamethasone-induced or phorbol myristate acetate-induced killing of thymocytes. Immobilized R13 by itself could not induce thymocyte apoptosis. Soluble R13 enhanced CD3-mediated apoptosis when HSA and T-cell receptor (TCR)/CD3 were co-cross-linked by a cross-reactive secondary antibody. Even without the cross-reactive secondary antibody, soluble R13 enhanced CD3-mediated apoptosis, although a greater than 100-fold increase in the amount of R13 was needed to give a similar enhancement compared with immobilized R13. Neither R13 by itself nor R13 plus secondary antibody induced cytosolic calcium influx, whereas R13 enhanced CD3-mediated cytosolic calcium increase. These results suggest a functional role of HSA in promoting the activation-induced apoptosis of thymocytes and the involvement of HSA in negative selection.

Animals↗
PubMed1998

Use of TCR ADV gene segments by the delta chain is independent of their position and of CD3 expression.

The CD3 signaling complex is required for cell surface expression and selection of both alphabeta and gammadelta TCR. In this study we analyzed TCRD transcripts in both wild-type and CD3-epsilon-deficient mice. We show that the repertoire of ADV segments used by the delta chain is unchanged in the latter. Not all ADV genes participate in making up the TCRD repertoire. However, their use does not depend on their distance from the other TCRD-forming segments. For example ADV12, situated at more than 870 kb from the DD region, is expressed as part of TCRD transcripts, whereas ADV8, members of which are proximal to the DD region, is not. These data suggest that the accessibility of ADV8 gene segments is differentially regulated during T cell development in the thymus. Taken together, our results suggest that TCRA and TCRD rearrangements are independently controlled, and that the absence of TCRA expression in CD3-epsilon-deficient mice is not due to a lack of accessibility of the ADV gene segments but rather to inaccessibility of the AJ gene region.

Animals↗