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At least 451 records · Page 25Linked to original sources
PubMed2001

Hypothermia attenuates beta1 integrin expression on extravasated neutrophils in an animal model of meningitis.

Brain injury in meningitis occurs in part as a consequence of leukocyte migration and activation. Leukocyte integrins are pivotal in the inflammatory response by mediating adhesion to vascular endothelium and extracellular matrix proteins. We have demonstrated that moderate hypothermia early in the course of meningitis decreases leukocyte sequestration within the brain parenchyma. This study examines whether hypothermia alters neutrophil integrin expression in a rabbit model of bacterial meningitis. Prior to the induction of meningitis, peripheral blood samples were obtained and the neutrophils isolated. Sixteen hours after inducing group B streptococcal meningitis, animals were treated with antibiotics, i.v. fluids, and mechanically ventilated. Animals were randomized to hypothermia (32-33 degrees C) or normothermia conditions. After 10 hours of hypothermia or normothermia, neutrophils were isolated from the blood and cerebral spinal fluid (CSF), stained for beta1 and beta2 integrins, and analyzed using flow cytometry. Cerebral spinal fluid neutrophil beta1 integrin expression was significantly decreased in hypothermic animals. Beta-1 integrins can assume a higher affinity or "activated" state following inflammatory stimulation. Expression of "activated" beta1 integrins was also significantly decreased in hypothermic animals. Beta2 CSF neutrophil integrin expression was decreased in hypothermic animals, but failed to reach significance. These data suggest hypothermia may attenuate extravasated leukocyte expression of both total and "activated" beta1 integrins.

Animals↗
PubMed1996

The inhibitory anti-beta1 integrin monoclonal antibody 13 recognizes an epitope that is attenuated by ligand occupancy. Evidence for allosteric inhibition of integrin function.

Integrin-ligand binding causes conformational changes in the integrin, as evidenced by the increased expression of epitopes known as ligand-induced binding sites. Some monoclonal antibodies (mAbs) that recognize ligand-induced binding sites stimulate ligand binding, possibly by stabilizing the ligand-occupied conformation of the integrin. Here we have investigated the effect of ligand recognition by alpha5beta1 on the binding of a mAb that inhibits beta1 integrin function (mAb 13). Ligand (fibronectin fragment or GRGDS peptide) decreased the binding of mAb 13 to alpha5beta1. Analysis of this inhibition showed that at high ligand concentrations, approximately 50% of the total integrin bound mAb 13 with >50-fold lower affinity than in the absence of ligand. The concentration of ligand required for half-maximal inhibition of antibody binding was independent of antibody concentration, suggesting that ligand acts as an allosteric inhibitor of mAb 13 binding. Hence, ligand and mAb 13 did not appear to compete directly for binding to alpha5beta1. The stimulatory anti-beta1 mAb 9EG7 was found to increase the maximum level of ligand binding approximately 2-fold, indicating that up to 50% of the total integrin could not bind ligand without 9EG7 stimulation. Analysis of mAb 13 binding in the presence of 9EG7 and ligand (i.e. maximal ligand occupancy) demonstrated that essentially all of the integrin bound mAb 13 with very low or zero affinity. Our results demonstrate that mAb 13 recognizes an epitope that is dramatically attenuated in the ligand-occupied form of alpha5beta1. Hence, since mAb 13 preferentially recognizes the unoccupied conformation of the integrin, the antibody may inhibit ligand binding by stabilizing the unoccupied state of alpha5beta1. In addition, we present evidence that the binding of mAb 13 to ligand-occupied alpha5beta1 may also induce a conformational change in the integrin, resulting in the displacement of ligand.

Allosteric Regulation↗
PubMed2004

The integrin beta1 subunit transmembrane domain regulates phosphatidylinositol 3-kinase-dependent tyrosine phosphorylation of Crk-associated substrate.

Our previous studies on the transmembrane domain of human integrin subunits have shown that a conserved basic amino acid in both subunits of integrin heterodimers is positioned in the plasma membrane in the absence of interacting proteins. To investigate the possible functional role of the lipid-embedded lysine in the mouse integrin beta1 subunit, this amino acid was replaced with leucine, and the mutated beta1 subunit (beta1A(K756L)) was stably expressed in beta1-deficient GD25 cells. The extracellular domain of beta1A(K756L) integrins possesses a competent conformation for ligand binding as determined by the ability to mediate cell adhesion, and by the presence of the monoclonal antibody 9EG7 epitope. However, the spreading of GD25-beta1A(K756L) cells on fibronectin and laminin-1 was impaired, and the rate of migration of GD25-beta1A(K756L) cells on fibronectin was reduced compared with GD25-beta1A cells. Phosphorylation of tyrosines in focal adhesion kinase (FAK) and the Y416 in c-Src in response to beta1A(K756L)-mediated adhesion was similar to that induced by wild-type beta1. The tyrosine phosphorylation level of paxillin, a downstream target of FAK/Src, was unaffected by the beta1 mutation, whereas tyrosine phosphorylation of CAS was strongly reduced. The results demonstrate that CAS is a target for phosphorylation both by FAK-dependent and -independent pathways after integrin ligation. The latter pathway was inhibited by wortmannin and LY294002, implicating that it required an active phosphatidylinositol 3-kinase. Furthermore, the K756L mutation in the beta1 subunit was found to interfere with beta1-induced activation of Akt. The results from this study identify phosphatidylinositol 3-kinase as an early component of a FAK-independent integrin signaling pathway triggered by the membrane proximal part of the beta1 subunit.

Amino Acid Sequence↗
PubMed2001

Distinct roles for dystroglycan, beta1 integrin and perlecan in cell surface laminin organization.

Dystroglycan (DG) is a cell surface receptor for several extracellular matrix (ECM) molecules including laminins, agrin and perlecan. Recent data indicate that DG function is required for the formation of basement membranes in early development and the organization of laminin on the cell surface. Here we show that DG-mediated laminin clustering on mouse embryonic stem (ES) cells is a dynamic process in which clusters are consolidated over time into increasingly more complex structures. Utilizing various null-mutant ES cell lines, we define roles for other molecules in this process. In beta1 integrin-deficient ES cells, laminin-1 binds to the cell surface, but fails to organize into more morphologically complex structures. This result indicates that beta1 integrin function is required after DG function in the cell surface-mediated laminin assembly process. In perlecan-deficient ES cells, the formation of complex laminin-1 structures is defective, implicating perlecan in the laminin matrix assembly process. Moreover, laminin and perlecan reciprocally modulate the organization of the other on the cell surface. Taken together, the data support a model whereby DG serves as a receptor essential for the initial binding of laminin on the cell surface, whereas beta1 integrins and perlecan are required for laminin matrix assembly processes after it binds to the cell.

Animals↗
PubMed2005

Endothelial-monocyte activating polypeptide II alters fibronectin based endothelial cell adhesion and matrix assembly via alpha5 beta1 integrin.

Mature Endothelial-Monocyte Activating Polypeptide (mEMAP) II functions as a potent antiangiogenic peptide. Although the anti-tumor effect of mEMAP II has been described, little is known regarding its mechanism of action. Observations that mEMAP II induced apoptosis only in a subset of migrating and proliferating endothelial cells (EC) suggests a targeted effect on cells engaged in angiogenic activities which are known to rely upon cell adhesion and migration. Indeed, we demonstrate that mEMAP II inhibited fibronectin (FN) dependent microvascular EC (MEC) adhesion and spreading and we show that this depends upon the alpha5 beta1 integrin. Immunofluorescence analysis demonstrated that mEMAP II-dependent blockade of FN-alpha5 beta1 interactions was associated with disassembly of both actin stress fiber networks and FN matrix. These findings suggest that mEMAP II blocks MEC adhesion and spreading on fibronectin, via a direct interaction with the integrin alpha5 beta1, thus implicating that alpha5 integrin may be a mediator of mEMAP II's antiangiogenic function.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Expression of beta1 integrin in relation to histological features in normal and neoplastic canine testicles.

The expression of the beta1 common chain of the VLA integrin subfamily was evaluated immunohistochemically in a series of five normal and 30 neoplastic canine testicles. The tumours, consisting of seminomas or Sertoli cell tumours, were classified according to WHO criteria as intraductal without signs of invasion, intraductal with signs of invasion, or diffuse. Expression of beta1 integrin decreased progressively from intraductal tumours without signs of invasion, to the diffuse type, in which immunolabelling was generally absent. In a few cases of diffuse neoplasia, groups of neoplastic cells exhibited strong positivity that was not restricted to the basal pole of the cell membrane. These results suggest that the expression of beta1 integrin was related to the histological tumour type, possibly reflecting a specific requirement for a reduction in integrin by neoplastic cells with infiltrative and metastatic potential.

Animals↗
PubMed2004

Stimulation-dependent recycling of integrin beta1 regulated by ARF6 and Rab11.

In comparison to the internalization pathways of endocytosis, the recycling pathways are less understood. Even less defined is the process of regulated recycling, as few examples exist and their underlying mechanisms remain to be clarified. In this study, we examine the endocytic recycling of integrin beta1, a process that has been suggested to play an important role during cell motility by mediating the redistribution of integrins to the migrating front. External stimulation regulates the endocytic itinerary of beta1, mainly at an internal compartment that is likely to be a subset of the recycling endosomes. This stimulation-dependent recycling is regulated by ARF6 and Rab11, and also requires the actin cytoskeleton in an ARF6-dependent manner. Consistent with these observations being relevant for cell motility, mutant forms of ARF6 that affect either actin rearrangement or recycling inhibit the motility of a breast cancer cell line.

ADP-Ribosylation Factor 6↗
PubMed2003

Ras oncogene directs expression of a differentially sialylated, functionally altered beta1 integrin.

Intense investigation has centered on understanding the regulation of integrin cell adhesion receptors. In the present study, we propose that variant N-glycosylation represents an important mechanism for regulation of beta1, but not beta3 or beta5 integrins. We find that expression of oncogenic ras in HD3 colonocytes causes increased alpha2-6 sialylation of beta1 integrins, whereas expression of dominant-negative ras induces decreased alpha2-6 sialylation, relative to cells with wild-type ras. In contrast, neither beta3 nor beta5 integrins are alpha2-6 sialylated, regardless of the state of ras activation. Results from RT-PCR analyses suggest that differential integrin sialylation is due to a ras-dependent alteration in the expression of ST6Gal I, the enzyme that adds alpha2-6-linked sialic acids. Cells that express differentially sialylated beta1 integrins exhibit altered adhesion to collagen I (a beta1 ligand), but not to vitronectin (a beta3 or beta5 ligand). Similarly, the enzymatic removal of cell surface sialic acids from control cells alters binding to collagen, but not to vitronectin. Finally, using a cell-free receptor/ligand-binding assay, we show that purified, desialylated alpha1beta1 integrins have diminished collagen-binding capability, providing strong evidence that sialic acids play a causal role in regulating beta1 integrin function.

Base Sequence↗
PubMed1998

Rat neutrophils express alpha4 and beta1 integrins and bind to vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1).

The alpha4 integrins, which are constitutively expressed on all human leukocyte subtypes except neutrophils, interact with vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cell adhesion molecule (MAdCAM-1) on endothelium to mediate selective recruitment of leukocyte subpopulations, other than neutrophils, to sites of inflammation. However, here we report that a different paradigm of leukocyte recruitment may exist in the rat. Flow cytometric analysis of rat neutrophils using a panel of monoclonal antibodies which recognize rat alpha4 and beta1 integrins showed consistent, low levels of expression. Although alpha4 was expressed at lower levels on neutrophils than all other rat leukocytes, this level of expression was sufficient to mediate significant levels of alpha4- and beta1-dependent neutrophil adhesion to rat and human VCAM-1, and alpha4-dependent, but beta1-independent, adhesion to human MAdCAM-1. These data suggest that rat neutrophils, unlike other species, may use alpha4 integrins to traffic to sites of inflammation in vivo.

Animals↗
PubMed1999

Beta1-integrins mediate Ca2+-signalling and T cell spreading via divergent pathways.

Interaction of Jurkat T-lymphocytes with two extracellular matrix (ECM) proteins of the basement membrane, laminin or collagen type IV, combined with poly-L-lysine resulted in a strong adhesion, a highly increased intracellular Ca2+-concentration ([Ca2]i), as compared to cells on laminin or collagen type IV alone and in spreading of the cells. The strong adhesion was independent of an increase in [Ca2+]i, was not mediated by a beta1-integrin, and was due to charge interaction between the positively charged polyaminoacid and the negatively charged cell surface. The latter was confirmed by substitution of poly-L-lysine by other positively charged polyaminoacids. In contrast, Ca+-signalling and spreading of the cells adhering to laminin or collagen type IV combined with poly-L-lysine was completely blocked by anti-beta1 mAb. However, spreading of the cells was independent of an increase in [Ca2+]i suggesting divergent signal transduction pathways leading to Ca2+-signalling and spreading of the cells. We elucidated these signal transduction pathways by inhibition of key enzymes involved. The tyrosine kinase inhibitor genistein blocked Ca2+-signalling as well as spreading, whereas inhibitors of PKC (calphostin C, GF109203x), PLCgamma (U73122) and PLA2 (bromophenacyl-bromide (BPB), 3-[4-octadecyl)benzoyl]acrylic acid (OBAA)) selectively blocked spreading of the cells.

Calcium Signaling↗
PubMed2006

beta1 integrins modulate p66ShcA expression and EGF-induced MAP kinase activation in fetal lung cells.

ShcA proteins mediate Erk1/Erk2 activation by integrins and epidermal growth factor (EGF), and are expressed as p46ShcA, p52ShcA, and p66ShcA. Although p52ShcA and p46ShcA mediate Erk1/Erk2 activation, p66ShcA antagonizes Erk activation. p66ShcA is spatially regulated during lung development, leading us to hypothesize that integrin signaling regulates p66ShcA expression and, consequently, EGF signaling. Fetal lung mesenchymal cells were isolated from E16 Swiss-Webster mice, stimulated with oligopeptide extracellular matrix analogs or anti-integrin antibodies, and subjected to ShcA Western analyses and EGF-stimulated Erk1/Erk2 kinase assays. p66ShcA expression was decreased by anti-alpha1 integrin antibody and DGEA collagen analog, and increased by anti-beta1, anti-alpha4, and anti-alpha5 integrin antibodies and RGDS fibronectin analog. Paradoxically, beta1 integrin stimulation increased EGF-induced Erk activation while increasing expression of the inhibitory p66ShcA isoform. This paradox was resolved by demonstrating that Erk inhibition attenuates integrin-mediated p66ShcA induction. These results suggest that p66ShcA is up-regulated as inhibitory feedback on integrin-mediated Erk activation.

Adaptor Proteins, Signal Transducing↗
PubMed1998

T lymphocytes from Sézary syndrome patients express beta1 integrins whose beta(1-6)-branched N-linked oligosaccharides reflect their adhesive capacity.

Sézary syndrome (Sz), characterized by slowly progressing clonal proliferation of CD4+, CD45 RO+ T cells, has several forms that are distinguished according to the epidermotropic properties of the pathological cells. In a recent paper (Derappe C, Haentjens G, Lemaire S, Feugeas JP, Lebbe C, Pasqualetto V, Bussel A, Aubery M, Néel D. Leukemia 1996;10:138), we observed that T lymphocytes from most of the Sézary patients [Szbeta(1-6)+] expressed high levels of beta(1-6)-GlcNAc-branched N-linked oligosaccharides while T lymphocytes from other patients [Szbeta(1-6)-] did not. Because this observation suggests the possibility of two forms of Sz, distinguished according to the expression rate of these glycans, we looked for a possible relationship between this expression rate and T-cell adhesiveness. Using an original protocol (Braut-Boucher F, Pichon J, Rat P, Adolphe M, Aubery M, Font J. J Immunol Methods 1995;178:41), we observed that T lymphocytes obtained from the Szbeta(1-6)+ patients adhered less to normal keratinocyte monolayers than T lymphocytes from Szbeta(1-6)- patients and normal donors. As assessed by FACS analysis, all the integrin-subunits studied were more expressed on Szbeta(1-6)-, especially alpha4, alpha5, beta1 and beta2, than on Szbeta(1-6)+ and normal lymphocytes. Although these results suggest that beta1- and beta2-integrin expression is involved in the adhesive properties of these T-cells, other factors, such as glycosylation, may also contribute. To demonstrate this possibility, we sought the presence of beta(1-6)-GlcNAc-branched N-linked oligosaccharides on beta1 integrins expressed by T lymphocytes from Sz patients. Immunoblot experiments, performed using the specific lectin from Phaseolus vulgaris (Leukoagglutinin form), showed that only the beta1 integrin subunit expressed by T lymphocytes from Szbeta(1-6)+ patients carried these glycans, supporting the concept of the involvement of T-cell glycosylation in the evolution of Sz.

Carbohydrate Conformation↗
PubMed1996

Signal transduction through the beta1 integrin family surface adhesion molecules VLA-4 and VLA-5 of human B-cell precursors activates CD19 receptor-associated protein-tyrosine kinases.

We demonstrate that the CD19 receptor associates with the beta1 family integrin receptors on human B-cell precursors as well as mature B-lymphocytes, and engagement of the beta1 family integrin receptors with monoclonal antibody homoconjugates leads to rapid activation of the CD19-associated protein-tyrosine kinases (PTK) and results in hyperphosphorylation of CD19 on tyrosine residues. Our findings prompt the hypothesis that homoconjugate-induced integrin clustering may effect the approximation and, by intermolecular cross-phosphorylation, activation of the CD19-associated PTK and subsequent tyrosine phosphorylation of the CD19 receptor. The ability of the beta1 family integrin receptors to transmit a biochemical signal triggering the CD19-linked multifunctional PTK pathway provides a possible explanation for the pleiotropic biologic responses generated though adhesive VLA-4- and VLA-5-mediated contacts.

Antigens, CD19↗
PubMed2005

Adhesion of different cell cycle human hepatoma cells to endothelial cells and roles of integrin beta1.

AIM: To investigate the adhesive mechanical properties of different cell cycle human hepatoma cells (SMMC-7721) to human umbilical vein endothelial cells (ECV-304), expression of adhesive molecule integrinbeta1 in SMMC-7721 cells and its contribution to this adhesive course. METHODS: Adhesive force of SMMC-7721 cells to endothelial cells was measured using micropipette aspiration technique. Synchronous G1 and S phase SMMC-7721 cells were achieved by thymine-2-deoxyriboside and colchicines sequential blockage method and double thymine-2-deoxyriboside blockage method, respectively. Synchronous rates of SMMC-7721 cells and expression of integrinbeta1 in SMMC-7721 cells were detected by flow cytometer. RESULTS: The percentage of cell cycle phases of general SMMC-7721 cells was 11.01% in G2/M phases, 53.51% in G0/G1 phase, and 35.48% in S phase. The synchronous rates of G1 and S phase SMMC-7721 cells amounted to 74.09% and 98.29%, respectively. The adhesive force of SMMC-7721 cells to endothelial cells changed with the variations of adhesive time and presented behavior characteristics of adhesion and de-adhesion. S phase SMMC-7721 cells had higher adhesive forces than G1 phase cells ((307.65+/-92.10) x 10(-10) N vs (195.42+/-60.72) x 10(-10) N, P<0.01). The expressive fluorescent intensity of integrinbeta(1) in G(1) phase SMMC-7721 cells was depressed more significantly than the values of S phase and general SMMC-7721 cells. The contribution of adhesive integrinbeta1 was about 53% in this adhesive course. CONCLUSION: SMMC-7721 cells can be synchronized preferably in G1 and S phases with thymine-2-deoxyriboside and colchicines. The adhesive molecule integrinbeta1 expresses a high level in SMMC-7721 cells and shows differences in various cell cycles, suggesting integrin beta1 plays an important role in adhesion to endothelial cells. The change of adhesive forces in different cell cycle SMMC-7721 cells indicates that S phase cells play predominant roles possibly while they interact with endothelial cells.

Carcinoma, Hepatocellular↗
PubMed2000

Expression of beta1-integrins and N-cadherin in bladder cancer and melanoma cell lines.

Changes in the expression of integrins and cadherins might contribute to the progression, invasion and metastasis of transitional cell cancer of the bladder and of melanomas. The expression of alpha5 (P < 0.001), alpha2 and beta1 (P < 0.05 - P < 0.001) integrin subunits in melanoma cells from noncutaneous metastatic sites (WM9, A375) were significantly increased as compared to cutaneous primary tumor (WM35) and metastatic (WM239) cell lines. These differences might be ascribed to the invasive character of melanoma cells and their metastasis to the noncutaneous locations. The significantly heterogeneous expression of beta1 integrin subunit in two malignant bladder cancer cell lines (T24 and Hu456) and nonsignificant differences in the expression of alpha2, alpha3, and alpha5 subunits between malignant and non-malignant human bladder cell lines do not allow an unanimous conclusion on the role of these intergrin subunits in the progression of transitional cancer of bladder. The adhesion molecule, expressed in all studied melanoma and bladder cell lines, that reacted with anti-Pan cadherin monoclonal antibodies was identified as N-cadherin except in the HCV29 non-malignant ureter cell line. However, neither this nor any other bladder or melanoma cell line expressed E-cadherin. The obtained results imply that the replacement of E-cadherin by N-cadherin accompanied by a simultaneous increase in expression of alpha2, alpha3 and alpha5 integrin subunits clearly indicates an increase of invasiveness of melanoma and, to a lesser extent, of transitional cell cancer of bladder. High expression of N-cadherin and alpha5 integrin subunit seems to be associated with the most invasive melanoma phenotype.

Antibodies, Monoclonal↗
PubMed1998

Identification of beta1C-2, a novel variant of the integrin beta1 subunit generated by utilization of an alternative splice acceptor site in exon C.

A new splice variant of the human integrin subunit beta1 has been identified and designated beta1C-2. It differs from the previously reported beta1C (in this report designated beta1C-1) by 18 nucleotides, and is generated by splicing from exon 6 to an alternative splice acceptor site within exon C, causing an in-frame deletion of six amino acids of the cytoplasmic region of beta1C-1. The beta1C-2 mRNA is present in several human cell lines and tissues at low levels, similarly to beta1C-1. In peripheral T-lymphocytes, beta1C-2 is the selectively expressed isoform. Neither beta1C-1 nor beta1C-2 mRNA could be detected in mouse tissues, and Southern hybridization of a mouse genomic beta1 clone with a human exon-C-specific probe failed to identify a corresponding mouse exon. The antisense orientation of exon C is highly homologous to an Alu element. Since Alu elements are restricted to primates, the beta1C-1 and beta1C-2 variants of the integrin subunit beta1 are specific for these species. The protein coded for by the beta1C-2 cDNA can be expressed and localized to the surface of beta1 deficient mouse cells. However, while stable transformed clones expressing high levels of the beta1A were commonly found, the beta1C-1 and beta1C-2 expressing clones expressed barely detectable amounts of the beta1 protein. Hence, high levels of beta1C-2 may be incompatible with cell proliferation, as previously suggested for beta1C-1.

Alternative Splicing↗
PubMed2001

Dopamine interacts directly with its D3 and D2 receptors on normal human T cells, and activates beta1 integrin function.

Dopamine by itself has not up to now been reported to activate T cell function. We show here that dopamine interacts directly with dopaminergic receptors on normal human T cells and triggers beta1 integrin-mediated T cell adhesion to a major extracellular matrix component, fibronectin (FN). Such adhesion is a characteristic feature of activated T cells, and is critical for trafficking and extravasation of T cells across blood vessels and tissue barriers. Seven dopamine D2/D3 receptor agonists and antagonists were used to identify the receptor subtypes with which dopamine specifically interacts to activate T cells. The D3 dopamine receptor agonist, 7-hydroxy-DPAT (DPAT), mimics the effects of dopamine, and the effects of both dopamine and DPAT are blocked by a specific D3 receptor antagonist, U-maleate. The dopamine receptor agonists bromocriptine and pergolide mimic the direct effect of dopamine on the beta1 integrin function, while the dopamine receptor antagonists butaclamol and haloperidol suppress it, suggesting additional signaling via the dopamine D2 receptor subtype. Our study shows, for the first time, that dopamine can directly activate T cells via ist specific receptors and suggests a possible role for dopamine in integrin-mediated cellular trafficking and extravasation of T cells in the central nervous system and possibly also in the periphery. Finally, we suggest that the reported changes in the D3 and D2 receptor RNA levels in peripheral blood lymphocytes of individuals with schizophrenia, Parkinson's disease, Alzheimer's disease and migraine can serve not only as a 'passive' diagnostic marker, but primarily reflect the dynamic functional dopamine-T cell interactions in these diseases.

Cell Adhesion↗
PubMed1999

Costimulation of CD28- T cells through CD3 and beta1-integrins induces a limited Th1 cytokine response.

The costimulatory molecule CD28 regulates antigen-specific T-cell proliferation and the synthesis of multiple cytokines. The absence of CD28 on a subset of CD8bright+ T cells suggests that these cells may utilize alternative costimulatory pathways or have a limited cytokine response to presented antigen. We used fibronectin, a ligand for the beta1-integrins alpha4beta1 and alpha5beta1, as an alternate costimulatory ligand to assess the functional phenotype of CD8bright+CD28- T cells. CD25 expression was significantly up-regulated in CD8bright+CD28- T cells by immobilized anti-CD3i with fibronectin. Costimulation with fibronectin also significantly augmented anti-CD3i-induced IFN-gamma production only among CD8bright+CD28- T cells. The CD8bright+CD28- T cells did not produce significant IL-2 and IL-10 even in response to maximal stimulation with phorbol myristate acetate and ionomycin. These data support a costimulatory role for ss1-integrins in CD8bright+CD28- T cells and indicate that CD8bright+ CD28- T cells have a restricted Th1 cytokine repertoire.

CD28 Antigens↗