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Query: UMLS:C0001511 (Adhesion)
 5,955 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Engagement of the TCR modulates the avidity of several receptors that play key roles in lymphocyte adhesion and/or signal transduction, including CD8, CD11a/CD18 (LFA-1), CD2, and several beta 1-integrins. Here, we investigated whether CD4+ T cells similarly undergo TCR-regulated adhesion to isolated MHC class II proteins through CD4. Strong adhesion of a number of CD4+ T cell clones to immobilized antigenic peptide/class II complexes was readily detectable. Adhesion to antigenic class II proteins was CD4 dependent and inhibited by pretreatment of T cells with the protein tyrosine kinase inhibitor herbimycin A, suggesting that adhesion requires TCR- and/or CD4-derived signal transduction. Treatment of T cells with anti-TCR Ab strongly increased subsequent adhesion to the extracellular matrix proteins, fibronectin and vitronectin, but, significantly, not to immobilized nonantigenic class II proteins. Suboptimal densities of antigenic peptide/class II complexes also activated adhesion of T cells to coimmobilized fibronectin or vitronectin, and this resulted in production of IFN-gamma to levels exceeding those stimulated by optimal densities of antigenic class II complexes alone. However, no augmentation of adhesion or cytokine secretion occurred when self or third party class II proteins were coimmobilized with antigenic class II complexes. The present results, therefore, suggest fundamental differences in the mechanism by which the TCR regulates coreceptor adhesion in CD4+ and CD8+ T cells.
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PMID:Murine CD4+ T cells undergo TCR-activated adhesion to extracellular matrix proteins but not to nonantigenic MHC class II proteins. 756 Oct 90

Adhesion of CD8+ CTL to purified class I proteins has been shown to be regulated by the TCR: nonactivated CTL do not adhere to immobilized class I proteins (non-Ag), but adhesion becomes readily detectable upon treatment of the CTL with fluid-phase anti-TCR mAb. Signals for up-regulating CD8 adhesion do not appear to involve products of the PI pathway, as neither increased production of inositol phosphates or mobilization of [Ca2+]i can be detected in response to the fluid-phase anti-TCR mAb, but both occur when the CTL then bind to class I protein. The lack of a role for phosphoinositide pathway products in up-regulating CD8 was confirmed by the inability of phorbol ester or calcium ionophore to substitute for TCR mAb in triggering adhesion to class I proteins. Instead, both phorbol ester and calcium ionophore inhibited the anti-TCR mAb-stimulated adhesion to class I. Inhibitors of protein tyrosine kinases also block TCR-activated, CD8-dependent adhesion to class I, and concomitantly block inositol phosphate release, Ca2+ mobilization and degranulation. Inhibition of signaling and response does not appear to be caused solely by the inhibition of adhesion to class I, however, because these inhibitors also block signaling in response to immobilized anti-TCR mAb under conditions in which binding of other receptors to their ligands is not necessary to initiate phosphoinositide hydrolysis and degranulation. These results lend further support for a model in which CTL activation involves a cascade of adhesion and signaling events initiated by the TCR and propagated by CD8 and additional cell-surface receptors.
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PMID:Signals for activation of CD8-dependent adhesion and costimulation in CTLs. 815 59

Activation of CTL requires engagement of both the TCR and the CD8 coreceptor. Immobilized class I proteins and in vitro-formed peptide class I Ag complexes have been used to examine the relative contributions of TCR and CD8 to the adhesion and response of cloned, class I-restricted CTL. The extent of degranulation was found to be directly proportional to the concentration of peptide used to pulse class I, suggesting that activation is a direct function of TCR occupancy level. In contrast, activation of degranulation as a function of the amount of class I on the surface displayed a marked threshold density dependence. Essentially the same density dependence was found for the response of CTL to fluid phase anti-TCR mAb and non-Ag class I, indicating that CD8-class I interaction must exceed a threshold before effective cosignaling can occur. Adhesion and degranulation of CTL was minimal in response to in vitro peptide-class I complexes prepared at a class I density below the threshold. However, the same density of peptide class I initiated both adhesion and response if additional non-Ag class I was coimmobilized on the same surface at levels above threshold. Thus, when surface levels of peptide class I complex are low, as is likely to be the case under physiologic conditions, the level of TCR occupancy achieved is, by itself, insufficient to mediate cell adhesion or activate degranulation. The results demonstrate, however, that low TCR occupancy is sufficient to provide the signal to prime CD8. Provided that the surface density of class I is sufficiently high, CD8 then mediates strong adhesion and provides the costimulatory signal(s) to activate response.
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PMID:Activation of CD8-dependent cytotoxic T lymphocyte adhesion and degranulation by peptide class I antigen complexes. 849 89

We studied the ability of a peptide mimicking the major binding site of HLA-DR beta 2 for CD4 (i.e. amino acids 134-148) to inhibit the adhesion of CD4+ T cells to B cells and ICAM-1-DR-expressing fibroblasts, as well as the proliferation of TCR-CD3-triggered CD4+ T cells. Peptide DR134-148 blocked CD4+ T cell (but not CD8+ T cell) binding to B cells and to DR+ ICAM-1+ fibroblasts in a concentration-dependent manner. A peptide composed of randomly associated identical amino acid residues had no effect. This inhibitory activity was not additive with the effect of an anti-CD4 antibody, peptide DR35-46 (mimicking another potential binding site of HLA-DR beta 1 to CD4) or an anti-LFA-1 antibody. Adhesion of a T cell line (HUT78) expressing a mutated form of CD4 unable to bind p56lck cytosine kinase was not inhibited by peptide DR134-148. In addition, herbimycin A, a tyrosine kinase inhibitor, abrogated the inhibitory activity of DR134-148. Since CD4-MHC class II interactions have been shown to play no detectable role in mediating antigen-independent adhesion in this assay, peptide interactions with CD4 may trigger an off signal down-regulating LFA-1-mediated adhesion. Indeed, adhesion of CD4+ T cells to ICAM-1- fibroblasts was not inhibited by peptide DR134-148, while the same peptide inhibited antigen (protein-pure derivative)- and anti-CD3 antibody-induced CD4 T cell proliferation. These findings suggest that the major sequence involved in the MHC class II interaction with CD4 is sufficient to induce a downstream negative regulatory signal that is mediated by p56lck, independently of antigen-specific TCR triggering.
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PMID:A synthetic peptide mimicking the HLA-DR beta 2-binding site for CD4 inhibits antigen-independent CD4+ T cell adhesion to B cells and CD4+ T cell activation. 867 12

T cell recognition of foreign Ag/MHC class II complexes is sensitive down to approximately 100 complexes per cell or approximately 0.2 complexes/micron2. To better understand the physical basis of the recognition stage of Ag presentation, we examined adhesion of the lysozyme- specific T cell hybridoma, 3A9, to artificial bilayers containing covalent MHC class II/peptide complexes or adhesion molecules. Adhesion of 3A9 cells required a superphysiologic density of the MHC class II/peptide complex and was partly dependent on CD4; cells adhered but did not crawl. No adhesion was observed to bilayers containing MHC class II molecules without the lysozyme peptide. Activated 3A9 cells adhered and crawled on bilayers containing ICAM-1. The physical strength of contacts was tested with fluid shear. 3A9 cells adherent to bilayers containing MHC class II/peptide complexes shed their contact, which remained on the substrate and contained TCR. In contrast, 3A9 cells peeled from the ICAM-1 bilayer, and held firmly on LFA-1 bilayers; in a manner dependent on filamentous actin. When ICAM-1 and the MHC/peptide complexes were combined, the 3A9 cells adhered tightly and spread, but did not crawl, on the bilayers and TCR clustered at the center of the contact area. Physiologically, the TCR is unlikely to directly initiate adhesion. TCR clusters formed with the assistance of adhesion mechanisms may have to be shed to allow de-adhesion, and this may contribute to TCR down-regulation.
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PMID:TCR-mediated adhesion of T cell hybridomas to planar bilayers containing purified MHC class II/peptide complexes and receptor shedding during detachment. 875 22

T cell adhesion induced after physiological stimulation by antigen was investigated using murine T cell hybridomas specific for a tetanus toxin peptide. By employing a novel assay, the T cell hybridomas were shown to strongly adhere to peptide-pulsed APC in a dose-dependent fashion. Adhesion peaked at 30-60 min and declined thereafter. This assay allowed us to study the relationship between T cell adhesion and later activation responses using tetanus toxin peptide and alanine monosubstituted analogs. We show that the degree of peptide-induced T cell adhesion correlated with the magnitude of late functional responses. CD4, LFA-1 (CD11a/CD18), and CD28 were critical in the adhesion response. The enhancing role of CD4 was further demonstrated by reduced levels of T cell adhesion and late responses of CD4- T cell hybridomas. Reexpression of CD4 reversed these defects. Our data suggest a link between antigen-induced T cell adhesion and late responses and also suggest that signals mediated by TCR and CD4 coengagement may induce a greater activation and/or recruitment of molecules involved in T cell adhesion.
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PMID:Induction of T cell adhesion by antigen stimulation and modulation by the coreceptor CD4. 891 73

The transmembrane protein tyrosine phosphatase CD45 is required for Ag receptor signal transduction in lymphocytes. Recently, a role for CD45 in the regulation of macrophage adhesion has been demonstrated as well. To investigate further the role of CD45 in the regulation of adhesion, we examined integrin-mediated adhesion to fibronectin of two T cell lines and their CD45-deficient variants. The absence of CD45 correlated with enhanced adhesion to fibronectin via integrin alpha5beta1 (VLA-5), but not alpha4beta1 (VLA-4) in both cell lines. Adhesion returned to normal levels upon transfection of wild-type CD45 into the CD45-deficient lines. Transfection of chimeric or mutant molecules expressing some, but not all, CD45 domains and activities demonstrated that both the transmembrane domain and the tyrosine phosphatase activity of CD45 were required for regulation of integrin-dependent adhesion, but the highly glycosylated extracellular domain was dispensable. In contrast, only a catalytically active CD45 cytoplasmic domain was required for TCR signaling. Transfectants that restored normal levels of adhesion to fibronectin coimmunoprecipitated with the transmembrane protein known as CD45-associated protein. These studies demonstrate a novel role for CD45 in adhesion regulation and suggest a possible function for its association with CD45-associated protein.
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PMID:Regulation of integrin-mediated T cell adhesion by the transmembrane protein tyrosine phosphatase CD45. 1035 56

Adhesion molecules are believed to facilitate infiltration of leukocytes into the CNS of mice with experimental allergic encephalomyelitis (EAE). The role of the adhesion molecule CD62L (L-selectin) in the immunopathology of EAE is not known. To study this, we crossed CD62L-deficient mice with myelin basic protein-specific TCR (MBP-TCR) transgenic mice. CD62L-deficient MBP-TCR transgenic mice failed to develop antigen-induced EAE, and, despite the presence of leukocyte infiltration, damage to myelin in the CNS was not seen. EAE could, however, be induced in CD62L-deficient mice upon adoptive transfer of wild-type macrophages. Our results suggest that CD62L is not required for activation of autoimmune CD4 T cells but is important for the final destructive function of effector cells in the CNS and support a novel mechanism whereby CD62L expressed on effector cells is important in mediating myelin damage.
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PMID:CD62L is required on effector cells for local interactions in the CNS to cause myelin damage in experimental allergic encephalomyelitis. 1129 Mar 38

Antigen detection and initiation of TCR signaling only occur, under physiological conditions, when T cells are adherent, and not in suspension. We show here that T cell adhesion causes an increase in the Ca(2+) content of intracellular stores and of the amount of phosphatidylinositol 4,5-bisphosphate in the plasma membrane, and enhances TCR-induced Ca(2+) signaling. This priming can be observed in freshly isolated T cells, in activated T cells, and in some T cell lines. Stimulation of T cells by specific monomeric MHC-peptide complexes only triggers Ca(2+) responses after T cell adhesion. This solves a controversial issue concerning the minimum valency of activatory TCR ligands. Adhesion-induced T cell priming not only occurs upon binding to artificial substrates such as immobilized ligands, but also upon interaction with dendritic cells. Thus, this phenomenon is likely to contribute to the high sensitivity of antigen detection by T cells in secondary lymphoid organs.
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PMID:T cell adhesion lowers the threshold for antigen detection. 1273 Oct 46

Initial adhesive contacts between T lymphocytes and dendritic cells (DCs) facilitate recognition of peptide-MHC complexes by the TCR. In this report, we studied the dynamic behavior of adhesion and Ag receptors on DCs during initial contacts with T-cells. Adhesion molecules LFA-1- and ICAM-1,3-GFP as well as MHC class II-GFP molecules were very rapidly concentrated at the DC contact area. Binding of ICAM-3, and ICAM-1 to a lesser extent, to LFA-1 expressed by mature but not immature DC, induced MHC-II clustering into the immune synapse. Also, ICAM-3 binding to DC induced the activation of the Vav1-Rac1 axis, a regulatory pathway involved in actin cytoskeleton reorganization, which was essential for MHC-II clustering on DCs. Our results support a model in which ICAM-mediated MHC-II clustering on DC constitutes a priming mechanism to enhance antigen presentation to T-cells.
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PMID:Synaptic clusters of MHC class II molecules induced on DCs by adhesion molecule-mediated initial T-cell scanning. 1587 88


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