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PubMed1995

Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling.

The alpha v beta 6 integrin was identified in cultured epithelial cells and functions as a fibronectin receptor. We have now used monoclonal antibodies to determine in vivo expression patterns of the beta 6 subunit in normal and pathological human or primate tissues, and during experimental wound healing or induced lung injury. The results indicate that beta 6 expression is restricted to epithelia and is up-regulated in parallel with morphogenetic events, tumorigenesis, and epithelial repair. During development of the kidney, lung, and skin, we found that beta 6 is expressed by specific types of epithelial cells, whereas it is mostly undetectable in normal adult kidney, lung and skin. In contrast, we detected high-level expression in several types of carcinoma. For example, beta 6 is almost invariably neo-expressed in squamous cell carcinomas derived from the oral mucosa, often focally localized at the infiltrating edges of tumor islands. Expression of beta 6 is also upregulated in migrating keratinocytes at the wound edge during experimental epidermal wound healing. Similarly, beta 6 expression is induced in type II alveolar epithelial cells during lung injury caused by injection of live bacteria. We also observed beta 6 expression in adult lungs and kidneys at focal sites of subclinical inflammation, as well as in a variety of clinical specimens from patients with chronic or acute inflammation of the lungs or kidneys. From these findings and earlier results, we hypothesize that alpha v beta 6 affects cell spreading, migration and growth during reorganization of epithelia in development, tissue repair, and neoplasia.

Animals↗
PubMed1996

Regulation of cell migration by the integrin beta subunit ectodomain.

CS-1 melanoma cells transfected with cDNAs encoding either the beta 3 or beta 5 integrin subunit protein express alpha v beta 3 or alpha v beta 5, respectively, enabling them to adhere to vitronectin yet only alpha v beta 3 promotes cell spreading and migration on this substrate. Following exposure to insulin or insulin-like growth factor, alpha v beta 5-expressing CS-1 cells gain the ability to migrate on vitronectin. To identify structural regions in beta 3 or beta 5 that account for these distinct biological properties, CS-1 cells were transfected with one of two chimeric beta subunit proteins, in which the ecto- and cytoplasmic domains of beta 3 and beta 5 were exchanged (termed alpha v beta 3/5 or alpha v beta 5/3). Surprisingly, alpha v beta 3/5 expressing cells spread and migrate on vitronectin while cells expressing alpha v beta 5/3 do not unless they are exposed to cytokine. These findings suggest that the distinct migratory properties mediated by integrins alpha v beta 3 and alpha v beta 5 and their response to cytokine activation is determined by a sequence(s) within the ectodomain of the integrin beta subunit.

Animals↗
PubMed1998

The integrin alphavbeta6 is critical for keratinocyte migration on both its known ligand, fibronectin, and on vitronectin.

The integrin alphavbeta6 is expressed on a variety of epithelial cells during dynamic processes including organogenesis, tissue injury and malignant transformation. However, because of the lack of tools to specifically inhibit the function of this integrin, little is known about its effects on cell behavior. To directly examine the role of this integrin in cell migration, we used keratinocytes derived from wild-type mice or mice expressing a null mutation in the beta6 subunit (beta6-/-) to perform migration assays in vitro. Migration on the known alphavbeta6 ligand, fibronectin was reduced in keratinocytes from beta6-/- mice. Interestingly, keratinocytes from beta6-/- mice also demonstrated markedly reduced migration on vitronectin, a protein not previously known to be a ligand for alphavbeta6. An anti-alphavbeta6 monoclonal antibody 10D5, generated by immunization of beta6-/- mice with murine keratinocytes, inhibited adhesion and migration of wild-type keratinocyte on both vitronectin and fibronectin to levels similar to those seen with keratinocytes from beta6-/- mice. alphavbeta6-mediated migration on both ligands was dramatically augmented by treatment with phorbol myrisate acetate (PMA) or with hepatocyte growth factor, and augmentation of migration by either stimulus could be abolished by the PKC inhibitor GF109203X, suggesting a critical role for PKC in enhancement of alphavbeta6-mediated cell migration.

Animals↗
PubMed1998

The vitronectin receptor associates with clathrin-coated membrane domains via the cytoplasmic domain of its beta5 subunit.

Rat myotubes cultured in fetal calf serum adhere to vitronectin-coated substrates through two distinct structures, focal contacts and clathrin-coated membrane domains. We studied the integrins in myotubes to learn how they associate with these two domains. Double label immunofluorescence studies with antibodies specific for clathrin, vinculin and several forms of integrin showed that focal contacts and clathrin-coated membrane domains contain both vitronectin receptors (VnR, containing beta-3 and beta-5integrins) and fibronectin receptors (FnR, containing beta1-integrin). VnR but not FnR associates tightly with the substrate in both domains, as the VnR alone remains attached to the coverslip when the lipid bilayer and other membrane proteins are removed by detergent. Ultrastructural studies confirmed the localization of the beta5 subunit of the VnR at both domains. We used intracellular injection and affinity chromatography to test the possibility that clathrin at coated membrane domains associates with the cytoplasmic sequence of the beta5 subunit of the VnR. Injection of a synthetic peptide containing the NPXY motif from the cytoplasmic domain of the human beta5 subunit, SRARYEMASNPLYRKPIST, depleted clathrin from coated membrane domains without affecting clathrin in perinuclear structures or vinculin at focal contacts. Injection of the homologous beta1 peptide, MNAKWDTGENPIYKSAVITT, also containing an NPXY motif, had no significant effect on any of these structures. Affinity matrices containing the beta5 but not the beta1 peptide selectively retained clathrin from myotube extract, and bound clathrin could be selectively eluted by soluble forms of the beta5 but not the beta1 peptide. Thus, a sequence including the NPXY motif in the integrin beta5 subunit is involved in the specific anchoring of the VnR, but not the FnR, to clathrin-coated membrane.

Amino Acid Sequence↗
PubMed1998

The alphavbeta5 integrin functions as an endocytic receptor for vitronectin.

Endocytosis and degradation of vitronectin by human skin fibroblasts are regulated by the beta5 integrin. To determine whether the beta5 integrin is directly mediating the internalization of vitronectin, both vitronectin and the beta5 integrin were localized by indirect immunofluorescence during the endocytic process. This analysis showed that both vitronectin and beta5 were found in intracellular vesicles within 5 minutes of the addition of exogenous vitronectin to fibroblast cell layers. By 15 minutes, approximately 20% of the vitronectin-containing vesicles stained positively for beta5. In contrast, the beta3 integrin was not found in any intracellular vesicles. Within 30 minutes, more than 50% of vitronectin-containing vesicles also stained for lamp-1, indicating that internalized vitronectin traveled to lysosomes. Inhibition of clathrin assembly by either potassium depletion or hypertonic buffer inhibited vitronectin internalization, suggesting that vitronectin internalization occurred through coated pits. Confocal analysis confirmed the colocalization of vitronectin and alphavbeta5 in intracellular compartments and further demonstrated that the highest colocalization of the two proteins occurred within 1.8 microm from the ventral surface of the cell, suggesting endocytosis occurred at the substrate level. Pretreatment of cells with the PI-3 kinase inhibitor, wortmannin, resulted in a marked increase in the coincidence of vitronectin and beta5 staining within vesicles and prevented the accumulation of vitronectin within lysosomes. This suggests that following internalization, vitronectin and the alphavbeta5 integrin are segregated to different cellular compartments. This study provides the first evidence that the alphavbeta5 vitronectin receptor directly mediates the internalization of vitronectin.

Androstadienes↗
PubMed1999

Amino acid motifs required for isolated beta cytoplasmic domains to regulate 'in trans' beta1 integrin conformation and function in cell attachment.

The role of beta cytoplasmic domains in regulating beta1 integrin conformation and function in cell attachment is not fully understood. In this study, we tested the ability of transiently expressed beta cytoplasmic domains connected to an extracellular reporter domain to regulate 'in trans' the conformation of endogenous beta1 integrins, and compared these effects on cell attachment. We found that chimeric receptors containing either the beta1, beta3 or beta5 cytoplasmic domains inhibited the expression of the conformationally dependent 9EG7 and 12G10 epitopes on endogenous beta1 integrins. In contrast, chimeric receptors containing the beta4 or alpha5 cytoplasmic domain, or a control receptor lacking a cytoplasmic domain, had no effect. This inhibition occurred in a dose-dependent manner that required high levels of expression of the chimeric receptor. These results suggest that beta1 integrin conformation can be regulated by conserved cytosolic interactions involving beta cytoplasmic domains. This is further supported by our findings that mutations within amino acid motifs conserved among these beta cytoplasmic domains, specifically the NXXY, NPXY and TST-like motifs, reduced the ability of these chimeric receptors to regulate beta1 integrin conformation. Interestingly, the chimeric receptors inhibited cell attachment in a similar dose-dependent manner and required intact NXXY, NPXY, and TST-like motifs. The beta1 chimera also inhibited the binding of soluble fibronectin to endogenous beta1 integrins. Thus, the concomitant inhibition in the expression of conformation-dependent integrin epitopes, cell attachment and ligand binding by the chimeras, suggests that the expression of the 9EG7 and 12G10 epitopes correlates with integrin function. However, Mn2+, which is an extracellular activator of integrin function, increased 9EG7 expression to basal levels in the presence of the beta1 chimera, but did not rescue cell attachment to the same extent. Thus, although the beta1 integrin conformation recognized by mAb 9EG7 may be required for cell attachment, it is not sufficient, suggesting that the beta chimeras may be inhibiting both ligand binding and post-ligand binding events required for cell attachment. In addition, the inhibitory effects of the chimeric receptors on cell attachment were not reversed by the addition of the pharmacological agents that inhibit intracellular signals previously shown to inhibit integrin function. This finding, together with the requirement for high levels of the chimeric receptors and the fact that mutations in the same conserved motifs in heterodimeric beta1 integrins have been reported to regulate beta1 integrin conformation and function in cell attachment, suggest that beta cytoplasmic domains regulate these processes by interacting with cytosolic factors and that the regulatory effect of the chimeras may be due to their ability to titrate proteins from endogenous integrins.

Amino Acid Sequence↗
PubMed2004

Mice lacking the integrin beta5 subunit have accelerated osteoclast maturation and increased activity in the estrogen-deficient state.

UNLABELLED: Integrin alphavbeta5 is expressed on osteoclast precursors and is capable of recognizing the same amino acid motif as alphavbeta3. Three-month-old beta5(-/-) female OVX mice had increased osteoclastogenesis ex vivo, and microCT assessment of trabecular bone volume was 53% lower than WT-OVX animals. These preliminary data suggest alphavbeta5 integrin's presence on osteoclast precursors may inhibit of osteoclast formation. INTRODUCTION: Osteoclasts are unique resorptive skeletal cells, capable of degrading bone on contact to the juxtaposed matrix. Integrin alphavbeta5 is expressed on osteoclast precursors, structurally similar to alphavbeta3, and capable of recognizing the same amino acid motif. Given the structural relationship and reciprocal regulation of alphavbeta3 and alphavbeta5, the purpose of this study was to evaluate how alphavbeta5 might contribute to osteoclast maturation and activity. MATERIALS AND METHODS: Three-month-old wildtype (WT) and beta5(-/-) female mice had ovariectomy (OVX) or sham operations. The osteoclastogenic capacity of marrow-derived precursors, the kinetic, the circulating, and structural parameters of bone remodeling, was determined after 6 weeks of paired feeding. RESULTS AND CONCLUSIONS: OVX increased osteoclastogenesis ex vivo and in vivo. Osteoclast formation and prolonged pre-osteoclast survival were substantially enhanced in cultures containing beta5(-/-) cells whether obtained from sham-operated or OVX mice. Expression of cathepsin K, beta3 integrin subunit, and calcitonin receptor were accelerated in cultured beta5(-/-)osteoclasts. beta5(-/-) osteoclasts from OVX animals showed a 3-fold enhancement of net resorptive activity, with quantitative muCT showing trabecular bone volume loss after OVX 53% greater in beta5(-/-) OVX compared with similarly treated WT OVX mice (p < 0.05). alpha5beta3 seems to be an inhibitor of osteoclast formation, in contrast to alphavbeta3. In addition, loss of alphavbeta5 seems to accelerate osteoclast formation in the OVX model. Further examination of alphavbeta5 signaling pathways may enhance our understanding of the activation of bone resorption.

Animals↗
PubMed2004

Characterization of the expression of key adenoviral receptors CAR and integrin beta3/beta5 subunits on the membrane of human NT2 neurons.

Expression of therapeutic gene products in differentiated human NT2 neurons (NT2/Ns) is being explored for ex vivo gene therapy of human neurological diseases. In this study we determined the efficiency of adenovirus (Ad)-mediated gene delivery into NT2/Ns and characterized the expression of several key receptors known to be required for efficient Ad-mediated gene delivery. Undifferentiated NT2 cells and NT2/Ns were infected by Ad expressing green fluorescent protein at an efficiency of 33% and 17%, respectively percentages much lower than the 92% infectivity obtained from a human non-neuronal cell line A549 cells. This relatively low infectivity of NT2/Ns might be caused by the extremely low expression of integrin subunit beta3 and the reduced expression of beta5 during differentiation. The expression of coxsackie-Ad receptor (CAR) was relatively high and remained constant during differentiation. Blocking CAR receptor using an antibody specific against CAR reduced Ad infectivity in a dose-dependent manner. These observations suggest that modulating the expression of integrin subunits beta3/5 or the functional heterodimer alphavbeta3/5 in human NT2/Ns may enhance adenoviral infectivity of NT2/Ns.

Adenoviridae↗
PubMed1999

The PlA2 polymorphism of the platelet glycoprotein IIIA gene as a risk factor for acute renal allograft rejection.

Glycoprotein IIIa/IIb is a membrane receptor for fibrinogen and von Willebrand factor that plays an important role in platelet aggregation. The beta integrin chain of this receptor, GPIIIa, is polymorphic, and the allele known as PlA2 has been associated with coronary thrombosis. The GPIIIa genotype of a cohort of 119 consecutive renal allograft recipients (46.3 +/- 13 yr; 85 M/34 F; 24.4% diabetic patients) was determined by PCR-restriction fragment length polymorphism, and those patients were followed for at least 12 mo. From 119 patients with at least 1 yr of follow-up, those who suffered an acute rejection (n = 52) showed a lower proportion of HLA-DR beta1 identity with the donor (7.7% versus 23.9%; P = 0.03), a higher proportion of cytomegalovirus-positive (CMV+) donors/CMV- recipients (21% versus 7.5%; P = 0.05), and the PlA2 allele was more frequent (48.1% versus 26.9%; P = 0.02) compared with patients free of acute rejection (n = 67). No other variable was associated with acute rejection in the univariate analysis. The impact of the three above-mentioned significant variables on acute rejection was analyzed by stepwise logistic regression. The presence of the PlA2 allele yielded an odds ratio of 2.75 (95% confidence interval, 1.01 to 7.93) and an HLA-DR beta1 identity of 0.2 (95% confidence interval, 0.06 to 0.99) for suffering an acute rejection episode. In addition, the serum creatinine at discharge was higher in PlA2-positive versus PlA2-negative patients (2.2 +/- 1.6 versus 1.5 +/- 0.6 mg/dl, respectively; P = 0.01), and the prevalence of proteinuria >1.5 g/d 1 yr after transplantation was significantly higher among patients showing the PlA2 allele (16% versus 3%; P = 0.02). Finally, in the entire cohort of patients, the 2-yr graft survival was significantly lower in PlA2-positive (n = 43) compared with PlA2-negative (n = 76) patients (85.7% versus 97.2%; P = 0.015). No differences were found in patient survival (95.2% versus 98.7%, respectively). Proportional hazards regression analysis (Cox regression model) confirmed that serum creatinine level at discharge is the best predictor of allograft survival, followed by CMV status, delayed graft function, and the glycoprotein IIIa/IIb genotype. The PlA2 polymorphism is an independent risk factor for acute renal graft rejection, affecting short-term graft survival. Future studies aimed at preventing the hemostatic imbalance favoring platelet aggregation associated with this polymorphism may be important in preventing acute rejection and its impact on chronic rejection.

Acute Disease↗
PubMed2000

Mouse beta(6) integrin sequence, pattern of expression, and role in kidney development.

Integrins mediate cell-cell and cell-extracellular matrix interactions and play key roles in development. beta(6) integrin expression has been demonstrated in human fetal kidney at a higher level than in the adult, making beta(6) integrin a marker of interest for the study of development of the nephron. The aims of this study were to determine the cDNA sequence for the mouse beta(6) integrin and to characterize beta(6) integrin expression in the developing mouse kidney. Two embryonic mouse kidney cDNA libraries were screened, and the coding region was sequenced. The mouse beta(6) nucleotide coding region sequence shows 82% nucleotide identity to the human sequence. The putative amino acid sequence has 89.5% identity to human beta(6) integrin and contains many conserved domains. By reverse transcription-PCR, beta(6) integrin mRNA expression is very low at 11 d of gestation in the mouse, increases dramatically by E14 and E17 (20-fold, normalized for increases in ss actin), and plateaus by 2 wk of age. beta(6) integrin expression is induced 15- to 20-fold after 5 d in metanephric explant culture. Reverse transcription-PCR of adult rat microdissected nephron segments demonstrates ss(6) integrin mRNA expression in proximal tubule, cortical thick ascending limb, distal nephron segments (inner and outer medullary collecting ducts), and macula densa-containing segments. Lectin-peroxidase and in situ colocalization studies demonstrated expression of ss(6) integrin mRNA in developing proximal tubules and thick ascending limb. Culture of mouse metanephric kidneys with antisense oligonucleotides to beta(6) integrin resulted in inhibition of ureteric bud branching and complete lack of mesenchyme condensation. These studies demonstrate a high homology between the human and mouse beta(6) integrin sequence, a different pattern of expression in the developing mouse kidney compared with the primate kidney, and abnormal metanephric development in culture in the absence of beta(6) integrin. These findings suggest an important role for beta(6) integrin in normal development of the mouse kidney.

Aging↗
PubMed1996

Mucosa-associated (beta 7-integrinhigh) lymphocytes accumulate early in the pancreas of NOD mice and show aberrant recirculation behavior.

The mucosal addressin cell adhesion molecule-1 (MAdCAM-1) becomes expressed on islet vessels of NOD mice early during lymphocyte accumulation in islets. Because MAdCAM-1 preferentially mediates the homing of mucosal lymphocytes, islet-associated MAdCAM-1 could favor the accumulation of mucosal lymphocytes in pancreatic islets. Therefore, we investigated the relative frequency of islet-infiltrating lymphocytes with a mucosal phenotype (alpha 4/beta 7-integrinhigh and L-selectinlow) at early and advanced stages of insulitis. We found that until the age of 12 weeks, lymphocytes with a mucosal phenotype were particularly frequent in the pancreas (percentage of beta 7-integrinhigh-lymphocytes was 48% at 8 weeks and 73% at 12 weeks), whereas in diabetic mice older than 16 weeks, their relative number was smaller (26% of pancreas-infiltrating lymphocytes). To define the origin and homing behavior of beta 7-integrinhigh-lymphocytes before their accumulation in pancreatic islets in NOD mice, we sought for such lymphocytes in different lymphoid organs and studied their recirculation. We found that compared with lymphocytes in several other strains, in NOD mice such lymphocytes were most frequent in nonmucosal lymphoid tissues (peripheral and pancreatic lymph nodes, spleen) from an early age. When injected to blood circulation, mucosal beta 7high-lymphocytes failed to home efficiently back to mucosal lymphoid tissue in NOD mice but homed aberrantly to nonmucosal lymphoid tissues. After adoptive transfer of diabetogenic splenocytes, the first lymphocytes accumulating in the pancreas were predominantly beta 7-integrinhigh. We conclude that mucosa-associated lymphocytes are involved in the early phases of islet-inflammation in NOD mice and that the aberrant homing behavior of lymphocytes expressing high levels of beta 7-integrin may associate with their accumulation in pancreatic islets early during insulitis.

Aging↗
PubMed2006

Expression and function of C/EBP homology protein (GADD153) in podocytes.

Podocytes are crucial for the permeability of the glomerular filtration barrier. In glomerular disease, however, reactive oxygen species (ROS) may be involved in podocyte injury and subsequent proteinuria. Here, we describe ROS-dependent gene induction in differentiated podocytes stimulated with H(2)O(2) or xanthine/xanthine-oxidase. Superoxide anions and H(2)O(2) increased mRNA and protein expression of GAS5 (growth arrest-specific protein 5) and CHOP (C/EBP homology protein). Cultured podocytes overexpressing CHOP showed increased generation of superoxide anions compared to controls. In addition, the expression of alpha(3)/beta(1) integrins, crucial for cell-matrix interaction of podocytes, was down-regulated, leading to increased cell-matrix adhesion and cell displacement. The altered cell-matrix adhesion was antagonized by the ROS scavenger 1,3-dimethyl-2-thiourea, and the increase in cell displacement could be mimicked by stimulating untransfected podocytes with puromycin, an inductor of ROS. We next performed immunohistochemical staining of human kidney tissue (normal, membranous nephropathy, focal segmental glomerulosclerosis, and minimal change nephropathy) as well as sections from rats with puromycin nephrosis, a model of minimal change nephropathy. CHOP was weakly expressed in podocytes of control kidneys but up-regulated in most proteinuric human kidneys and in rat puromycin nephrosis. Our data suggest that CHOP-via increased ROS generation-regulates cell-matrix adhesion of podocytes in glomerular disease.

Animals↗
PubMed1994

Mucosa specific lymphocytes in the human conjunctiva, corneoscleral limbus and lacrimal gland.

Conjunctiva associated lymphoid tissue shows several similarities to mucosa associated lymphoid tissue of the gut and respiratory tract. These similarities have been described in relation to lymphocyte subpopulations and epithelial cell morphology. However, unlike the lymphoid tissue of the gut and respiratory tract, mucosa specific lymphocytes have not been described in the ocular mucosa. In this study we demonstrated the presence of mucosa specific lymphocytes bearing the Human Mucosal Lymphocyte-1 antigen (beta 7 integrin), in the human conjunctiva, limbus and lacrimal gland. The distribution of this subset of lymphocytes corresponded to the distribution of CD8+ T-cells and was found maximally in the epithelium of the epibulbar conjunctiva and in the lacrimal gland. The Human mucosal lymphocyte antigen may function to determine mucosal homing of this particular subset of CD8+ T-cells, which in turn, may have special function in immunological defense and tolerance mechanisms occurring at mucosal surfaces.

Adolescent↗
PubMed1995

Differential mRNA regulation of integrin subunits alpha V, beta 1, beta 3, and beta 5 during mouse embryonic organogenesis.

Cell interactions with extracellular matrices play important roles in morphogenetic processes during embryonic development. Extracellular matrix receptors of the integrin family have been implicated in these steps. Recent studies indicate that a variety of integrins can be differentially expressed during development, consistent with diverse roles for integrins in embryogenesis. The present study compares the expression patterns of several major members of the alpha V integrin subfamily, focusing on mRNA expression of alpha V, beta 1, beta 3, and beta 5 subunits during mouse embryonic organogenesis using Northern blot analysis and in situ hybridization. The alpha V and beta 1 subunits showed widespread tissue expression, although most tissues expressed alpha V at relatively low or basal levels. The mRNA for beta 5 was also expressed in a variety of embryonic organs and showed unusual localization patterns in certain organs. Striking, high-level expression of beta 5 transcripts was detected in the ependymal layer of the central nervous system, glomeruli of the kidney, epicardial region of the heart, and in the tooth germs, suggesting specific functions for this molecule during morphogenetic events in these organs. In contrast, few beta 3 transcripts were expressed during mid-gestation mouse embryogenesis except in megakaryocytes within the embryonic liver. These observations of differing expression spectra suggest that members of the alpha V integrin subfamily have distinct roles and also suggests that they have different transcriptional regulation. The beta 5 integrin is unique in its degree of tissue-specific mRNA regulation associated with morphogenesis of embryonic organs.

Animals↗
PubMed2000

Up-regulation of VCAM-1 and differential expansion of beta integrin-expressing T lymphocytes are associated with immunity to pulmonary Mycobacterium tuberculosis infection.

Immune responses rely on an intricate system of adhesion molecules to coordinate the homing and retention of lymphocytes in both secondary lymphoid tissues and at sites of infection. To define the events associated with pulmonary immune responses, the expression of endothelial addressins and integrins on T cells was analyzed during Mycobacterium tuberculosis infection. In infected lung, expression of endothelial VCAM-1, but not mucosal addressin cell adhesion molecule-1, was up-regulated from 4 wk postinfection and persisted to at least 12 wk. Subsequent analysis of the corresponding integrins expressed on lung CD4+ and CD8+ T cells revealed an accumulation of beta1high/beta7-/low, and to a lesser extent beta7high, integrin-expressing T cells during infection. Examination of integrin heterodimers showed that while alpha4 integrin was predominantly expressed on beta1high/beta7-/low cells, alphaE integrin was primarily associated with beta7high. The majority of activated/memory T cells recruited during infection expressed high levels of beta1 integrin and undetectable or low levels of beta7 integrin. These T cells were capable of producing IFN-gamma, a cytokine crucial for controlling M. tuberculosis infection. Rapid expansion of beta1high, beta7-, and beta7high T cell populations in the lung upon secondary mycobacterial infection indicates the participation of these populations in the acquired immune response to the infection. Furthermore, treatment of infected mice with mAb to alpha4 or alpha4beta7 integrin led to a reduction in lymphocytes and increase in granulocytes in the pulmonary infiltrate. These results reveal a crucial role for adhesion molecules in the generation of an effective pulmonary immune response to M. tuberculosis infection.

Animals↗
PubMed2000

Maturation-dependent expression and function of the CD49d integrin on monocyte-derived human dendritic cells.

Dendritic cells (DC) are highly specialized APC that are critical for the initiation of T cell-dependent immune responses. DC exert a sentinel function while immature and, after activation by inflammatory stimuli or infectious agents, mature and migrate into lymphoid organs to prime T cells. We have analyzed integrin expression on monocyte-derived DC (MDDC) and found that expression of CD49d integrins (CD49d/CD29 and CD49d/beta7) was induced/up-regulated during TNF-alpha- or LPS-initiated MDDC maturation, reflecting the induction/up-regulation of CD49d and beta7 mRNA. CD49d mRNA steady-state level increased more than 10 times during maturation, with the highest levels observed 24 h after TNF-alpha treatment. CD49d integrin expression conferred mature MDDC with an elevated capacity to adhere to the CS-1 fragment of fibronectin, and also mediated transendothelial migration of mature MDDC. Up-regulation of CD49d integrin expression closely paralleled that of the mature DC marker CD83. CD49d integrin expression was dependent on cell maturation, as its induction was abrogated by N:-acetylcysteine, which inhibits NF-kappaB activation and the functional and phenotypic maturation of MDDC. Moreover, CD49d integrin up-regulation and MDDC maturation were prevented by SB203580, a specific inhibitor of p38 mitogen-activated protein kinase, but were almost unaffected by the mitogen-activated protein/extracellular signal-related kinase kinase 1/2 inhibitor PD98059. Our results support the existence of a link between functional and phenotypic maturation of MDDC and CD49d integrin expression, thus establishing CD49d as a maturation marker for MDDC. The differential expression of CD49d on immature and mature MDDC might contribute to their distinct motility capabilities and mediate mature DC migration into lymphoid organs.

Acetylcysteine↗
PubMed2001

Direct analysis of the dynamics of the intestinal mucosa CD8 T cell response to systemic virus infection.

The CD8 T cell response to vesicular stomatitis virus infection was characterized in the spleen and intestinal mucosa using MHC tetramers. Surprisingly, the primary response persisted in the lamina propria long after the splenic response had declined. Furthermore, the response was characterized by a protracted effector phase in which cytolytic activity in the lamina propria, but not in the spleen, was maintained. The appearance of Ag-specific cells in the intestinal mucosa was largely, though not exclusively, a result of beta(7) integrin-mediated migration. Infection with Listeria monocytogenes or with vaccinia virus also led to sustained mucosal responses. After reinfection of vesicular stomatitis virus-primed mice with a serotypically distinct virus, a sustained recall response was detected in all tissues. In CD40(-/-) mice, the mucosal, but not the splenic, response was compromised, resulting in diminished mucosal memory. The recall response was CD40 independent and correlated with memory levels, indicating that the mucosal and systemic responses operated independently. These findings illustrated the integrated yet distinct nature of systemic vs mucosal immune responses.

Animals↗