αL-Integrin I domain cyclic peptide antagonist selectively inhibits T cell adhesion to pancreatic islet microvascular endothelium

2005 ◽  
Vol 288 (1) ◽  
pp. G67-G73 ◽  
Author(s):  
Meng Huang ◽  
Kametra Matthews ◽  
Teruna J. Siahaan ◽  
Christopher G. Kevil
Keyword(s):  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
Cell Surface ◽  
Pancreatic Islet ◽  
Cyclic Peptide ◽  
Monocyte Adhesion ◽  
Cell Rolling ◽  
Tnf Α ◽  
Islet Endothelium

Insulitis is a hallmark feature of autoimmune diabetes that ultimately results in islet β-cell destruction. We examined integrin requirements and specific inhibition of integrin structure in T cell and monocyte adhesion to pancreatic islet endothelium. Examination of cell surface integrin expression on WEHI 7.1 T cells revealed prominent expression of β-, β1-, αL-integrins, and low expression of αM-integrins; whereas WEHI 274.1 monocytes showed significant staining for β2-, β1-, αM-molecules and no expression of αL-molecules. Unstimulated islet endothelium showed constitutive levels of ICAM-1 counter-ligand expression with minimal VCAM-1 expression; however, TNF-α stimulation increased cell surface density of both molecules. TNF-α increased T cell and monocyte rolling and adhesion under hydrodynamic flow conditions. Administration of a cyclic peptide competitor for the αL-integrin I domain binding sites (cyclo1,12-PenITDGEATDSGC) blocked T cell adhesion without inhibiting monocyte adhesion. Examination of T cell rolling revealed that cLAB.L treatment increased the average rolling velocity on activated endothelium and significantly decreased the fraction of T cells rolling at ≤50 μm/s, suggesting that cLAB.L treatment interferes with signal activation events required for the conversion of T cell rolling to firm adhesion. These data demonstrate for the first time that cyclic peptide antagonists against αL-integrin I domain attenuate T cell recruitment to islet endothelium.

Regulation of epithelial and lymphocyte cell adhesion by adenosine deaminase–CD26 interaction

2002 ◽  
Vol 361 (2) ◽  
pp. 203-209 ◽  
Author(s):  
Silvia GINÉS ◽  
Marta MARIÑO ◽  
Josefa MALLOL ◽  
Enric I. CANELA ◽  
Chikao MORIMOTO ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
B Cells ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Cell Surface ◽  
Adenosine Deaminase ◽  
Cell To Cell Adhesion ◽  
Lymphocyte Cell

The extra-enzymic function of cell-surface adenosine deaminase (ADA), an enzyme mainly localized in the cytosol but also found on the cell surface of monocytes, B cells and T cells, has lately been the subject of numerous studies. Cell-surface ADA is able to transduce co-stimulatory signals in T cells via its interaction with CD26, an integral membrane protein that acts as ADA-binding protein. The aim of the present study was to explore whether ADA—CD26 interaction plays a role in the adhesion of lymphocyte cells to human epithelial cells. To meet this aim, different lymphocyte cell lines (Jurkat and CEM T) expressing endogenous, or overexpressing human, CD26 protein were tested in adhesion assays to monolayers of colon adenocarcinoma human epithelial cells, Caco-2, which express high levels of cell-surface ADA. Interestingly, the adhesion of Jurkat and CEM T cells to a monolayer of Caco-2 cells was greatly dependent on CD26. An increase by 50% in the cell-to-cell adhesion was found in cells containing higher levels of CD26. Incubation with an anti-CD26 antibody raised against the ADA-binding site or with exogenous ADA resulted in a significant reduction (50–70%) of T-cell adhesion to monolayers of epithelial cells. The role of ADA—CD26 interaction in the lymphocyte—epithelial cell adhesion appears to be mediated by CD26 molecules that are not interacting with endogenous ADA (ADA-free CD26), since SKW6.4 (B cells) that express more cell-surface ADA showed lower adhesion than T cells. Adhesion stimulated by CD26 and ADA is mediated by T cell lymphocyte function-associated antigen. A role for ADA—CD26 interaction in cell-to-cell adhesion was confirmed further in integrin activation assays. FACS analysis revealed a higher expression of activated integrins on T cell lines in the presence of increasing amounts of exogenous ADA. Taken together, these results suggest that the ADA—CD26 interaction on the cell surface has a role in lymphocyte—epithelial cell adhesion.

scholarly journals Regulatory role of CD43 leukosialin on integrin-mediated T-cell adhesion to endothelial and extracellular matrix ligands and its polar redistribution to a cellular uropod

Blood ◽  
1995 ◽  
Vol 86 (6) ◽  
pp. 2228-2239 ◽  
Author(s):  
P Sanchez-Mateos ◽  
MR Campanero ◽  
MA del Pozo ◽  
F Sanchez-Madrid
Keyword(s):  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
Cell Surface ◽  
Adhesion Molecule ◽  
Negative Regulator ◽  
Regulatory Role ◽  
Beta 2 ◽  
T Lymphoblasts ◽  
T Cell Adhesion

CD43 is a cell surface-associated mucin that is abundantly expressed by most leukocytes, and that appears to function as a negative regulator of cell surface interactions, providing a repulsive barrier around cells. We have analyzed herein the ability of anti-CD43 monoclonal antibody (MoAb) to upregulate both beta 1 and beta 2 integrin-mediated cell adhesion and to promote redistribution of the CD43 molecule into a cellular uropod. Engagement of CD43 with specific antibodies enhanced the cell adhesion to both 80- and 38-kD fibronectin fragments as well as to the endothelial cell ligands vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, an effect that was mediated through the alpha 5 beta 1, alpha 4 beta 1, and alpha L beta 2 integrins, respectively. This effect on cell adhesion was achieved in Jurkat leukemic T cells by anti-CD43 MoAb alone; however, in T lymphoblasts, the activation of cell adhesion required the concomitant ligation of CD3 with suboptimal doses of anti-CD3 MoAb. Immunofluorescence analysis showed that the engagement of CD43 was accompanied by a differential redistribution of CD43 into a well- defined cytoplasmic projection or uropod, whereas the beta 1 or beta 2 integrins remained uniformly located on the contact area with substrata. This change in the localization of CD43 did not require costimulation and was induced directly by engagement of CD43 in T lymphoblasts. Other stimuli of cell adhesion in the form of cross- linked anti-CD3 MoAb or phorbol esters did not induce uropod formation or CD43 redistribution. In addition, we observed that prolonged co- culture of resting peripheral blood T lymphocytes with endothelial cells, in the absence of anti-CD43 MoAb, induced uropod formation and redistribution of CD43 in T cells. Interestingly, the myosin-disrupting drug butanedione monoxime inhibited the redistribution of CD43 induced by the specific MoAb, whereas the stimulation of cell adhesion induced by engagement of CD43 was preserved in the presence of this drug. These observations indicate that the signaling inducing integrin-mediated cell adhesion by CD43 takes place independently from the receptor redistribution. Altogether, these results indicate that CD43 has a regulatory role on both integrin-mediated T-cell adhesion and cellular morphology.

scholarly journals Patterns for RANTES Secretion and Intercellular Adhesion Molecule 1 Expression Mediate Transepithelial T Cell Traffic Based on Analyses In Vitro and In Vivo

1998 ◽  
Vol 187 (12) ◽  
pp. 1927-1940 ◽  
Author(s):  
Masahiko Taguchi ◽  
Deepak Sampath ◽  
Takeharu Koga ◽  
Mario Castro ◽  
Dwight C. Look ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
Cell Surface ◽  
Immune Cell ◽  
Intercellular Adhesion Molecule ◽  
Airway Epithelial ◽  
Intercellular Adhesion Molecule 1 ◽  
Ifn Γ

Immune cell migration into and through mucosal barrier sites in general and airway sites in particular is a critical feature of immune and inflammatory responses, but the determinants of transepithelial (unlike transendothelial) immune cell traffic are poorly defined. Accordingly, we used primary culture airway epithelial cells and peripheral blood mononuclear cells to develop a cell monolayer system that allows for apical-to-basal and basal-to-apical T cell transmigration that can be monitored with quantitative immunofluorescence flow cytometry. In this system, T cell adhesion and subsequent transmigration were blocked in both directions by monoclonal antibodies (mAbs) against lymphocyte function-associated antigen 1 (LFA-1) or intercellular adhesion molecule 1 (ICAM-1) (induced by interferon γ [IFN-γ] treatment of epithelial cells). The total number of adherent plus transmigrated T cells was also similar in both directions, and this pattern fit with uniform presentation of ICAM-1 along the apical and basolateral cell surfaces. However, the relative number of transmigrated to adherent T cells (i.e., the efficiency of transmigration) was increased in the basal-to-apical relative to the apical-to-basal direction, so an additional mechanism was needed to mediate directional movement towards the apical surface. Screening for epithelial-derived β-chemokines indicated that IFN-γ treatment caused selective expression of RANTES (regulated upon activation, normal T cell expressed and secreted), and the functional significance of this finding was demonstrated by inhibition of epithelial–T cell adhesion and transepithelial migration by anti-RANTES mAbs. In addition, we found that epithelial (but not endothelial) cells preferentially secreted RANTES through the apical cell surface thereby establishing a chemical gradient for chemotaxis across the epithelium to a site where they may be retained by high levels of RANTES and apical ICAM-1. These patterns for epithelial presentation of ICAM-1 and secretion of RANTES appear preserved in airway epithelial tissue studied either ex vivo with expression induced by IFN-γ treatment or in vivo with endogenous expression induced by inflammatory disease (i.e., asthma). Taken together, the results define how the patterns for uniform presentation of ICAM-1 along the cell surface and specific apical sorting of RANTES may serve to mediate the level and directionality of T cell traffic through epithelium (distinct from endothelium) and provide a basis for how this process is precisely coordinated to route immune cells to the mucosal surface and maintain them there under normal and stimulated conditions.

scholarly journals Synergistic T cell activation via the physiological ligands for CD2 and the T cell receptor.

1988 ◽  
Vol 168 (3) ◽  
pp. 1145-1156 ◽  
Author(s):  
B E Bierer ◽  
A Peterson ◽  
J C Gorga ◽  
S H Herrmann ◽  
S J Burakoff
Keyword(s):  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
Cell Surface ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Cytoplasmic Domain ◽  
Hla Dr

T cells may be activated either by the antigen-specific T cell receptor (TCR)-CD3 complex or the cell surface receptor CD2. A natural ligand for CD2 has been found to be lymphocyte function-associated antigen 3 (LFA-3), a widely distributed cell surface glycoprotein. To investigate the interaction of these two pathways, we have expressed the cDNA encoding the human CD2 molecule in a murine T cell hybridoma that produces IL-2 in response to HLA-DR antigens. Expression of the CD2 molecule markedly enhances IL-2 production in response to LFA-3+ antigen-bearing stimulator cells, and this stimulation is inhibited by anti-CD2 and anti-LFA-3 mAb. To further define the role of LFA-3 in antigen-dependent T cell activation, we have studied the ability of the purified ligands of CD2 and the TCR to stimulate the hybridoma. Neither liposomes containing purified HLA-DR antigens nor liposomes containing purified LFA-3 were able to stimulate the parent or the CD2+ hybridoma. However, liposomes containing both purified LFA-3 and HLA-DR, the physiological ligands for CD2 and the TCR, respectively, stimulate IL-2 production by the CD2+ but not the parent hybridoma, suggesting that complementary interactions between the TCR-CD3 complex and the CD2 pathway may regulate lymphocyte activation. To determine whether the CD2/LFA-3 interaction participates in cell-cell adhesion and provides an activation signal, we have constructed a cytoplasmic deletion mutant of CD2, CD2 delta B, in which the COOH-terminal 100 amino acids of CD2 have been replaced with a serine. Hybridomas expressing the CD2 delta B molecule were examined. Deletion of the cytoplasmic domain of CD2 did not alter binding of LFA-3 but eliminated the ability of CD2 to increase the response of the hybridoma to liposomes containing both HLA-DR and LFA-3, demonstrating that adhesion of LFA-3 to CD2 alone was insufficient for activation, and that the cytoplasmic domain was required for LFA-3 stimulation through the CD2 molecule. T cells may be activated by purified LFA-3 binding to CD2 and the TCR interacting with its ligand, and these signals appear to be synergistic for the T cell. These results suggest that the CD2/LFA-3 interaction not only plays a role in cell-cell adhesion but provides a stimulatory signal for T cell activation.

scholarly journals The induction of 72-kD gelatinase in T cells upon adhesion to endothelial cells is VCAM-1 dependent.

1994 ◽  
Vol 125 (5) ◽  
pp. 1165-1178 ◽  
Author(s):  
A M Romanic ◽  
J A Madri
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
Endothelial Cell ◽  
T Cell ◽  
Cell Surface ◽  
Cell Monolayer ◽  
Brain Parenchyma ◽  
Protein Activity ◽  
Gelatinase Activity

T cell extravasation from the bloodstream into the perivascular tissue during inflammation involves transmigration through the endothelial cell layer and basement membrane into the interstitial matrix. The specific mechanisms by which T cells transmigrate, however, are poorly understood. Matrix degradation by enzymes such as 72-kD gelatinase has been implicated as an important component in tissue invasion by various types of cells. In this study, we have demonstrated that 72-kD gelatinase is induced in T cells upon adhesion to endothelial cells. We also provide evidence that the induction of 72-kD gelatinase is mediated by binding to vascular cell adhesion molecule-1 (VCAM-1). The T cells used in this study were cloned murine Th1 cells antigenic to myelin basic protein. These cells express very late antigen-4 on their cell surface and have been shown to infiltrate the brain parenchyma and cause experimental autoimmune encephalomyelitis when infused into normal mice (Baron, J. L., J. A. Madri, N. H. Ruddle, G. Hashim, and C. A. Janeway. 1993. J. Exp. Med. 177:57-68). In the experiments presented here, T cells were cocultured with VCAM-1-positive and -negative endothelial cells grown in a monolayer in order to study the expression of 72-kD gelatinase upon T cell adhesion. Additional experiments were conducted in which T cells were cocultured with VCAM-1 positive cells grown on microporous membranes suspended in transwells to study 72-kD gelatinase following T cell transmigration. T cells were also incubated with recombinant VCAM-1 in order to study the role of VCAM-1 in inducing 72-kD gelatinase. The results demonstrated that T cells adhered to both VCAM-1-positive and -negative endothelial cells. T cells that adhered to the VCAM-1-positive endothelial cells exhibited an induction in 72-kD gelatinase protein, activity, and mRNA whereas 72-kD gelatinase was not induced in the T cells that adhered to the VCAM-1-negative endothelial cells. Incubating T cells with recombinant VCAM-1 coated onto tissue culture plastic showed that T cells adhered to the molecule and that adhesion to recombinant VCAM-1 was sufficient to induce 72-kD gelatinase. Further, T cells that had transmigrated through a VCAM-1-positive endothelial cell monolayer exhibited 72-kD gelatinase activity but not mRNA expression. In addition, 72-kD gelatinase was detected on the cell surface of the transmigrated T cells by FACS analysis. In other experiments, TIMP-2 was added to the transmigration studies and was shown to reduce T cell transmigration.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Longitudinal Changes in Cd4+, Cd8+ T Cell Phenotype and Activation Marker Expression Following Antiretroviral Therapy Initiation among Patients with Cryptococcal Meningitis

2019 ◽  
Vol 5 (3) ◽  
pp. 63
Author(s):  
Alice Bayiyana ◽  
Samuel Okurut ◽  
Rose Nabatanzi ◽  
Godfrey Zziwa ◽  
David R. Boulware ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Cell Surface ◽  
Cd8 T Cells ◽  
Cryptococcal Meningitis ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Effector Memory ◽  
Memory Subset

Despite improvement in the prognosis of HIV/AIDS (human immunodeficiency virus/acquired immune deficiency syndrome) patients on antiretroviral therapy (ART), cryptococcal meningitis (CM) still causes 10–15% mortality among HIV-infected patients. The immunological impact of ART on the CD4+ and CD8+ T cell repertoire during cryptococcal co-infection is unclear. We determined longitudinal phenotypic changes in T cell subsets among patients with CM after they initiated ART. We hypothesized that ART alters the clonotypic phenotype and structural composition of CD4+ and CD8+ T cells during CM co-infection. For this substudy, peripheral blood mononuclear cells (PBMC) were isolated at four time points from CM patients following ART initiation during the parent study (ClinicalTrials.gov number, NCT01075152). Phenotypic characterization of CD4+ and CD8+ T cells was done using T cell surface marker monoclonal antibodies by flow cytometry. There was variation in the expression of immunophenotypic markers defining central memory (CD27+CD45R0+), effector memory (CD45R0+CD27–), immune activation (CD38+ and Human Leucocyte Antigen DR (HLA-DR+), and exhaustion (Programmed cell death protein one (PD-1) in the CD4+ T cell subset. In comparison to the CD4+ T cell population, the CD8+ central memory subset declined gradually with minimal increase in the effector memory subset. Both CD4+ and CD8+ T cell immune exhaustion and activation markers remained elevated over 12 weeks. The relative surge and decline in the expression of T cell surface markers outlines a variation in the differentiation of CD4+ T cells during ART treatment during CM co-infection.

scholarly journals CCL19 enhances CD8+ T-cell responses and accelerates HBV clearance

2021 ◽  
Author(s):  
Yan Yan ◽  
Wei Zhao ◽  
Wei Liu ◽  
Yan Li ◽  
Xu Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Crucial Role ◽  
Cell Activation ◽  
Hbv Infection ◽  
Host Immune System ◽  
Tnf Α ◽  
Ifn Γ ◽  
High Level

Abstract Background Chemokine (C–C motif) ligand 19 (CCL19) is a leukocyte chemoattractant that plays a crucial role in cell trafficking and leukocyte activation. Dysfunctional CD8+ T cells play a crucial role in persistent HBV infection. However, whether HBV can be cleared by CCL19-activated immunity remains unclear. Methods We assessed the effects of CCL19 on the activation of PBMCs in patients with HBV infection. We also examined how CCL19 influences HBV clearance and modulates HBV-responsive T cells in a mouse model of chronic hepatitis B (CHB). In addition, C–C chemokine-receptor type 7 (CCR7) knockdown mice were used to elucidate the underlying mechanism of CCL19/CCR7 axis-induced immune activation. Results From in vitro experiments, we found that CCL19 enhanced the frequencies of Ag-responsive IFN-γ+ CD8+ T cells from patients by approximately twofold, while CCR7 knockdown (LV-shCCR7) and LY294002 partially suppressed IFN-γ secretion. In mice, CCL19 overexpression led to rapid clearance of intrahepatic HBV likely through increased intrahepatic CD8+ T-cell proportion, decreased frequency of PD-1+ CD8+ T cells in blood and compromised suppression of hepatic APCs, with lymphocytes producing a significantly high level of Ag-responsive TNF-α and IFN-γ from CD8+ T cells. In both CCL19 over expressing and CCR7 knockdown (AAV-shCCR7) CHB mice, the frequency of CD8+ T-cell activation-induced cell death (AICD) increased, and a high level of Ag-responsive TNF-α and low levels of CD8+ regulatory T (Treg) cells were observed. Conclusions Findings in this study provide insights into how CCL19/CCR7 axis modulates the host immune system, which may promote the development of immunotherapeutic strategies for HBV treatment by overcoming T-cell tolerance.

Structural and ICAM-1-Docking Properties of a Cyclic Peptide from the I-domain of LFA-1: An inhibitor of ICAM-1/LFA-1-mediated T-cell adhesion

2002 ◽  
Vol 19 (5) ◽  
pp. 789-799 ◽  
Author(s):  
Christine R. Xu ◽  
Helena Yusuf-Makagiansar ◽  
Yongbo Hu ◽  
Seetharama D.S. Jois ◽  
Teruna J. Siahaan
Keyword(s):  
Cell Adhesion ◽  
T Cell ◽  
Cyclic Peptide ◽  
T Cell Adhesion

CD56+ human blood dendritic cells effectively promote TH1-type γδ T-cell responses

Blood ◽  
2009 ◽  
Vol 114 (20) ◽  
pp. 4422-4431 ◽  
Author(s):  
Georg Gruenbacher ◽  
Hubert Gander ◽  
Andrea Rahm ◽  
Walter Nussbaumer ◽  
Nikolaus Romani ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Human Blood ◽  
Γδ T Cells ◽  
Rapid Expansion ◽  
Γδ T Cell ◽  
Hla Dr ◽  
Tnf Α ◽  
Ifn Γ

Abstract CD56+ human dendritic cells (DCs) have recently been shown to differentiate from monocytes in response to GM-CSF and type 1 interferon in vitro. We show here that CD56+ cells freshly isolated from human peripheral blood contain a substantial subset of CD14+CD86+HLA-DR+ cells, which have the appearance of intermediate-sized lymphocytes but spontaneously differentiate into enlarged DC-like cells with substantially increased HLA-DR and CD86 expression or into fully mature CD83+ DCs in response to appropriate cytokines. Stimulation of CD56+ cells containing both DCs and abundant γδ T cells with zoledronate and interleukin-2 (IL-2) resulted in the rapid expansion of γδ T cells as well as in IFN-γ, TNF-α, and IL-1β but not in IL-4, IL-10, or IL-17 production. IFN-γ, TNF-α, and IL-1β production were almost completely abolished by depleting CD14+ cells from the CD56+ subset before stimulation. Likewise, depletion of CD14+ cells dramatically impaired γδ T-cell expansion. IFN-γ production could also be blocked by neutralizing the effects of endogenous IL-1β and TNF-α. Conversely, addition of recombinant IL-1β, TNF-α, or both further enhanced IFN-γ production and strongly up-regulated IL-6 production. Our data indicate that CD56+ DCs from human blood are capable of stimulating CD56+ γδ T cells, which may be harnessed for immunotherapy.

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