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At least 955 records · Page 53Linked to original sources
PubMed1992

Antigen-specific stimulation of T cell extracellular acidification by MHC class II-peptide complexes.

A specific T cell response to a preformed complex of detergent-solubilized MHC class II molecule and cognate antigenic peptide was observed by monitoring the extracellular acidification. An increase in this rate was observed when the resting 4R3.9 T cell clone specific for the peptide fragment MBP(1-14) of myelin basic protein was exposed to preformed detergent-solubilized IAk-MBP(1-14)A4 complexes. MBP peptide alone, IAk alone, or complexes of IAs-proteolipid protein(139-151) and IAd-OVA(323-339), did not cause significant increases in the acidification rates of the MBP(1-14)-restricted 4R3.9 T cell clone. In addition, BW 5147 T lymphoma cells, which lack TCR, did not show any increase in rate when exposed to IAk-MBP(1-14)A4 complexes. Similar increases in acidification rate were observed in the presence of IL-2, anti-CD3 and anti-TCR antibodies. The enhanced acidification responses were blocked by genistein, a tyrosine kinase inhibitor.

Acids↗
PubMed1987

T3-T cell receptor (Ti) complex-independent activation of T cells by wheat germ agglutinin.

The T3-Ti complex appears to play a central role in the activation of T cells by antigens and mitogens. Wheat germ agglutinin (WGA) is a unique lectin which inhibits T cell proliferation induced by mitogens, but it also induces marked IL 2 production by peripheral blood T cells. The pattern of responses induced by WGA suggests that this lectin may use a different mechanism of T cell activation other than the mechanism employed by the common T cell stimulants. We first investigated the production of IL 2 by Jurkat cells (E6-1) stimulated with WGA, before and after modulation of the surface T3-Ti complex. IL 2 production was markedly reduced after modulation of the T3 antigen from the cell surface when these cells were stimulated with PHA. In contrast, little change was observed in WGA-induced IL 2 production after modulation. Furthermore, we examined the effect of WGA on a T3-mutant of E6-1 cells (T3.1) which does not produce IL 2 in response to PHA or PHA plus PMA. WGA-stimulated T3.1 cells produced a significant amount of IL 2 with or without added PMA. In addition, a small but consistent rise in intracytoplasmic free calcium was observed when these cells were stimulated with WGA. These results demonstrate the presence of an alternative mechanism of T cell activation independent of the T3-Ti complex.

Acetylglucosamine↗
PubMed1992

New insights into T-cell antigen receptor structure and signal transduction.

Recent studies have provided insights into how the complex structure of the T-cell antigen receptor relates to its signal transduction function. Both the CD3 and zeta subunits contain functioning signaling modules that regulate the activation of tyrosine kinases and phosphorylation of cellular substrates.

Amino Acid Sequence↗
PubMed1996

Mice infected with the larvae of Taenia crassiceps exhibit a Th2-like immune response with concomitant anergy and downregulation of Th1-associated phenomena.

Infection of intermediate hosts with eggs of taeniid parasites results in a larval infestation known as cysticercosis. A number of studies have indicated that cysticercosis is associated with immunosuppression, although little is known about the mechanisms involved. In the present study, mice infected with the larvae of Taenia crassiceps were found to exhibit a pronounced energy, which preferentially affected T-cells located anatomically close to the parasite. This anergy was linked to late events in the T cell activation pathway; that is, stimulation through the T cell receptor(TCR)/CD3 complex by Concanavalin-A, or plate-bound monoclonal antibodies (mAb) to TCR alpha beta or CD3 epsilon, or combinations of phorbol ester and ionomycin (all of which can bypass early membrane-related events), failed to fully activate T lymphocytes. The relative proximity of T cells to the parasite was directly related to upregulation of IL-4 and downregulation of IL-2 production. In addition, the profiles of parasite-specific Abs showed an exclusive increase of serum IgG1 during infection. Taken together, the data suggest that infection of mice with larvae of T. crassiceps alters the balance of CD4+ Th cells by upregulating Th2 and downregulating Th1 cells located in close proximity to the parasite.

Animals↗
PubMed1995

Phosphatidylinositol metabolism in lymphocytes of chronic alcoholic patients after anti-CD3 stimulation.

The immunological alterations observed in chronic alcoholic patients may be due to alterations of signal transduction across the lymphocyte membrane. Upon binding of mitogens or antigens to specific plasma membrane receptors, the activation of phospholipase C leads to the hydrolysis of inositol phospholipids, producing inositol phosphates and diacylglycerol. One of the early events in lymphocyte activation is an increase of intracellular calcium concentration, due to both an influx from extracellular fluid and a release from intracellular stores mediated by inositol phosphates. In this study we verified whether the diminished mobilization of intracellular calcium, previously observed in alcoholics, is caused by alteration in phosphoinositide turnover. We evaluated total inositol phosphate production in peripheral blood lymphocytes after anti-CD3 stimulation, comparing control subjects and alcoholic patients. Lymphocyte activation generated inositol phosphates in both controls and alcoholics, but to a different extent, inositol phosphate production being significantly higher in controls than in alcoholics. This reduction in inositol phosphate production could be accounted either to an inhibition of PLC activity or to a modified affinity of phospholipase C for its own substrates, i.e., phosphoinositides, which fatty acid composition has been previously demonstrated to be greatly different in alcoholics in comparison to healthy subjects.

Adult↗
PubMedDate not supplied

The short extracellular domain of the T cell receptor zeta chain is involved in assembly and signal transduction.

The zeta chain is required in the TCR complex to guarantee its surface expression and function. However, an understanding of the interaction(s) between the zeta chain and the other proteins in the TCR/CD3 has not yet been achieved. In this report, we attempt to assign a functional role to the short extracellular (EC) domain of the zeta chain by studying its unique positive charge, a lysine at position 9, because of its interesting location to the interchain disulphide bond of the zeta chain homodimer. We show that amino acid exchanges of lysine 9 to glycine, serine, cysteine or asparagine generate TCR complexes which are clearly defective in antigenic signalling. Interestingly, the non-conservative point mutations were segregating TCR complex signalling pathways. However, lysine 9 is not critical for TCR complex surface expression unless the positively charged lysine is exchanged for the negatively charged amino acid aspartic acid. The zeta chain mutant bearing a lysine to cysteine exchange is the sole mutant to be inefficiently co-precipitated with the TCR/CD3 complex suggesting a loose interaction of the zeta chain within the TCR complex.

Amino Acid Sequence↗
PubMed2002

Human immunedeficiency virus type 1 (HIV-1) disease progression may be due to defects in the expression of the TCR/CD3 complex as well as to a T CD4+ cell deficit.

The loss of T CD4+ cells leading to impairment of the immune system is the major cause of disease progression during HIV infection. More recently, the use of highly active anti-retroviral therapy (HAART) has raised important questions regarding the immune system restoration. Idiopathic CD4+ T lymphocytopenia syndrome (ICL) is similar to AIDS, except for the presence of HIV. Despite this similarity, ICL patients have a longer survival time than AIDS cases without HAART. The impairment of TCR/CD3-directed CD4+ T cell immune responses may be responsible for HIV disease progression. We think that the reduction of opportunistic infections which lead to death after HAART, is due to the ability of these memory clones to restore enough clones of the TCR/CD3 complex with fair capacity and diversity to confront frequent pathogens.

CD3 Complex↗
PubMed1992

A 68-kD GTP-binding protein associated with the T cell receptor complex.

The identity of the guanine nucleotide-binding protein (G protein) involved in T cell activation pathways remains unclear. We identified a 68-kD GTP-binding protein associated with the T cell receptor (TCR)/CD3 complex using immunoprecipitation and GTP-affinity labeling techniques. Proteins coimmunoprecipitated with the TCR/CD3 complex in digitonin lysate of a human leukemic T cell line, MOLT 16, were incubated with alpha-[32P]GTP and irradiated with ultraviolet rays to covalently link the labeled GTP to GTP-binding proteins. They were then analyzed by electrophoresis. The 68-kD protein exhibited nucleotide specificity for GTP-binding and was insensitive to cholera and pertussis toxins. The 68-kD GTP-binding protein could be coimmunoprecipitated with the TCR/CD3 complex but not with other surface molecules such as major histocompatibility complex class I and lymphocyte function associated-1, which do not cause rapid Ca2+ mobilization. These suggest that the 68-kD GTP-binding protein is specifically associated with the TCR/CD3 complex.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2005

D-enantiomer peptide of the TCRalpha transmembrane domain inhibits T-cell activation in vitro and in vivo.

T cell activation requires the cross-talk between the CD3-signaling complex and the T cell receptor (TCR). A synthetic peptide coding for the TCRalpha transmembrane domain (CP) binds CD3 molecules, interferes with the CD3/TCR cross-talk, and inhibits T cell activation. Intermolecular interactions are sterically constrained; accordingly no sequence-specific interactions are thought to occur between D- and L-stereoisomers. This argument was recently challenged when applied to intra-membrane protein assembly. In this paper we studied the ability of a D-stereoisomer of CP (D-CP) to inhibit T cell activation. L-CP and D-CP co-localized with the TCR in the membrane and inhibited T cell activation in a sequence-specific manner. In vivo, both L-CP and D-CP inhibited adjuvant arthritis. In molecular terms, these results suggest the occurrence of structural reorientation that facilitates native-like interactions between D-CP and CD3 within the membrane. In clinical terms, our results demonstrate that D-stereoisomers retain the therapeutic properties of their L-stereoisomers, while they benefit from an increased resistance to degradation.

Animals↗
PubMed1994

Imaging rheumatic joint diseases with anti-T lymphocyte antibody OKT-3.

T lymphocytes play an important role in the pathogenesis of rheumatoid arthritis (RA). Murine monoclonal antibody OKT-3 (IgG2a), known to be specific for T lymphocyte 20 kD glycoprotein CD3 receptor was labelled with 5 mCi 99Tcm and given intravenously (i.v.) to seven RA and two psoriatic arthritis patients following informed consent to identify inflamed synovium. Anterior and posterior whole body scans and specific regional imaging was commenced 20 min later. At 1 h, approximately 20% of 99Tcm was associated with the lymphocytes. In these patients, all 41 asymptomatic joints and 43 joints with mild pain or minimal tenderness had normal scans. All 34 joints with moderate to severe pain had moderate to marked uptake of radioactivity. Two patients experienced shaking chills for 20-30 min within an hour of 99Tcm-OKT-3 infusion. These results suggest that 99Tcm-OKT-3 imaging serves as an objective surrogate for joint inflammation and could be useful as a measurement of therapeutic effectiveness in RA and other diseases with inflamed synovium. The side effect profile may limit the utility of 99Tcm-OKT-3 but other forms of antibodies directed toward lymphocyte subsets may be useful.

Adult↗
PubMed2004

Multiparameter data acquisition and analysis of leukocytes.

For data acquisition, each supplier provides the software necessary and unique to its instrument. For data analysis, the same software may be used. In addition, several second party vendors provide software often with more capabilities than that provided by the instrument companies. Because of the increase in multiparameter data acquisition, we describe one method for validating instrument performance prior to data acquisition. The fundamentals of data analysis leading to a generic strategy for analysis of any number of parameters are described. This generic approach is designed to simplify the increasing complexity of multiparameter data analysis.

Animals↗
PubMed1991

CD59 functions as a signal-transducing molecule for human T cell activation.

The CD59 Ag is a 20-kDa protein that is widely expressed on most leukocytes and RBC, is coupled to the membrane by a phosphatidylinositol-glycan anchoring structure, plays a role in cell interaction between monocytes and T cells, and also functions as an inhibitor of cytolysis by the terminal C components C5b-9. Because this molecule is structurally related to the murine Ly-6 family of Ag, we have investigated whether anti-CD59 mAb might be capable of activating human T lymphocytes in a manner similar to that described for antibodies to the murine Ly-6 Ag. In the presence of the appropriate co-stimulators, mAb to one of the two epitopes on CD59 were capable of inducing both a rise in intracytoplasmic free Ca2+, inositol phosphate production, IL-2 production, and T cell proliferation. Anti-CD59-induced inositol phosphate turnover and IL-2 production were dependent on co-expression of the CD3/TCR complex. CD59-loss mutants of the Jurkat cell line were completely responsive to stimulation by anti-CD3 thereby demonstrating that CD59 does not play a role as a signal transducer downstream from the TCR. Taken together, these results demonstrate that the CD59 Ag can play multiple distinct roles in the regulation of the immune response.

Antibodies, Monoclonal↗
PubMed1990

Cellular mechanisms of lymphocyte-mediated lysis of tumor cells.

Both branches, humoral and cellular, of the immune response have specialized mechanisms to lyse tumor cells, virus-infected cells and other targets. The effector components of the humoral response are antibodies and complement, while cytotoxic T lymphocytes (CTL) and natural killer (NK) cells are among the potent effector agents of the cell-mediated immune response. The past few years have witnessed remarkable progress in defining the effector molecules and mechanisms involved in lymphocyte-mediated killing. The recognition of target cells by CTL is antigen specific and restricted through the major histocompatibility complex (MHC). The molecular structure involved in the recognition function is the T cell receptor (TCR), associated with CD3 polypeptides. Conversely, the activity of NK cells in non antigen specific and non MHC restricted. Several surface molecules of cytotoxic lymphocytes have been identified as adhesion-mediating structures. A particular role seems to be played by a family of molecules named lymphocyte function-associated antigens (LFA) and by CD2, CD4 and CD8 antigens. Once the binding between effector and target cell has occurred, a cascade of events can be triggered leading the killer lymphocyte to deliver the lethal hit against the target cell. At least two categories of cytolytic molecules are produced by CTL and NK cells. Perforin is a protein stored in the cytoplasmic granules which forms pores in the plasma membrane of target cell leading to osmotic lysis. The other category of cytolytic factors is the group of soluble mediators which includes lymphotoxin (LT), tumor necrosis factor (TNF) and NK cytotoxic factor (NKCF). Their exact mechanism of action is presently unclear. Several cellular components are involved in the cytolytic mechanism. In particular, the cytoplasmic granules which, upon activation, release a number of cytotoxic factors by directed exocytosis and the cytoskeletal components which, modifying their organization, participate in the binding and killing processes. A growing body of evidence has recently supplied proof that target cells may play an active role in their own lysis supporting the challenging opinion of an induced suicide mechanism.

Animals↗