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PubMed1998

Integrin-mediated interactions influence the tissue specificity of CD8+ cytolytic T lymphocytes.

We previously reported that CD8+ cytotoxic T lymphocytes (CTL) elicited in response to allogeneic renal epithelial cells (anti-REC CTL) preferentially lyse REC targets as compared to conventional lymphoid cell (LC) targets. It is often tacitly assumed that such cell type specificity results from CTL recognition of tissue-restricted MHC/peptide complexes. However, we herein report that anti-REC CTL uniquely express CD103, an integrin with known specificity for the epithelial cell-restricted ligand E-cadherin, and are deficient in expression of CD11a (LFA-1), an integrin known to play a critical accessory role in promoting lysis of LC targets. We demonstrate that CD8+ CTL clones with disparate CD103/CD11a phenotypes but identical specificities for allo-MHC/peptide can exhibit marked differences in cell type specificity. Antibody blocking studies provided direct evidence that CD103 serves as an accessory molecule that promotes lysis of REC targets. Taken together, these data indicate that integrin-mediated accessory interactions can influence the capacity of CD8+ CTL to discriminate between different cell types.

Animals↗
PubMed2000

Regulation of laminin-associated integrin subunit mRNAs in rat spinal motoneurons during postnatal development and after axonal injury.

Two important prerequisites for successful axon regeneration are that appropriate extracellular molecules are available for outgrowing axons and that receptors for such molecules are found in the regenerating neuron. Laminins and their receptors in the integrin family are examples of such molecules, and laminin-associated integrin subunits alpha 3, alpha 6, alpha 7, and beta 1 mRNAs have all been detected in adult rat motoneurons. We have here, by use of in situ hybridization histochemistry, examined the normal postnatal development of the expression in motoneurons of these mRNAs and integrin beta 4 mRNA, all of which have been associated with laminin-2. We studied the regulation of these mRNAs, 1-42 days after two types of axotomy in the adult rat (sciatic nerve transection, SNT; ventral root avulsion, VRA) and 1-10 days after SNT in the neonatal animal. During postnatal development, there was a distinct shift in the integrin composition from a stronger expression of the alpha 6 subunit to a very clear dominance of alpha 7 in the adult. All types of axotomy in the adult rat induced initial (1-7 days) large up-regulations of alpha 6, alpha 7 and beta1 subunit mRNAs (250-500%). Only minor changes for alpha 3 mRNA were seen, and beta 4 mRNA could not be detected at all in motoneurons. After adult SNT, the alpha 7 and beta 1 subunits were up-regulated throughout the studied period, and the alpha 6 subunit mRNA was eventually normalized. After VRA, however, the alpha 7 and beta1 levels peaked earlier than after SNT and were normalized at 42 days, whereas alpha 6 mRNA was up-regulated longer than after SNT. Neonatal SNT had much smaller effects on the expression of the studied subunits. The results suggest that an important part of the response to axotomy of motoneurons is to up-regulate receptors for laminin. The developmental shift in integrin subunit composition and the various responses seen in the lesion models indicate that different isoforms of laminin play a role in the regenerative response.

Animals↗
PubMed1995

Expression of the integrin subunit alpha 9 in the murine embryo.

The alpha 9 integrin subunit is expressed in adult skeletal muscle, visceral smooth muscle, hepatocytes, squamous epithelium, and airway epithelium. The in vivo function of this protein is unknown. Thus far, only a single alpha 9-containing integrin has been identified (alpha 9 beta 1) and only a single ligand (tenascin) has been found for this integrin. In order to gain insight into the potential function of alpha 9 integrin(s), we examined the spatiotemporal distribution of the alpha 9 subunit and tenascin during murine embryogenesis. In all tissues where alpha 9 was expressed, its appearance was associated with other evidence of cell differentiation. In developing airway, visceral, and vascular smooth muscles, the onset of alpha 9 expression either coincided with or immediately followed the expression of alpha-SM actin. Expression of alpha 9 in epithelia was restricted to the choroid plexus and the basal cell layer of squamous epithelia where its appearance coincided with the development of stratification. alpha 9 immunostaining was first detected in developing skeletal musculature when skeletal myotubes formed. Tenascin expression was detected in many, but not all tissues found to express alpha 9. For example, the hair germs of maturing hair follicles exhibited high levels of alpha 9 staining, but no tenascin immunoreactivity was detected either within the hair germ themselves or in the adjacent dermis. In some tissues where tenascin expression colocalized with alpha 9, expression patterns were not synchronous. Although alpha 9 expression was associated with the onset of tissue differentiation, its expression was not limited to terminally differentiated cells. In fact, in the skin, alpha 9 expression appeared restricted to cells known to retain the capacity to proliferate, i.e., basal cells and hair germs. Thus, alpha 9 integrin(s) are not likely to contribute to the early steps in organ formation, but probably play a role in the maturation and/or maintenance of a variety of differentiated tissues. The expression of alpha 9 without its only known ligand, tenascin, suggests the existence of additional ligands.

Animals↗
PubMed2002

Branch-specific migration cues in the Drosophila tracheal system.

The Drosophila tracheal system forms by highly stereotyped migration of the tracheal cells, generating an elaborate network of interconnected tubes supplying oxygen to all tissues. A major guiding system in the migration process of all branches is the dynamic and localized expression of Branchless (Bnl), an FGF-like molecule. Bnl triggers the activation of the FGF receptor Breathless (Btl) locally in all tracheal cells. Is this the only guiding cue, or do additional local signals provide distinct inputs to each branch? Several recent papers identify such local signals, relying on contacts with specific cell types and with the matrix encountered by the migrating tracheal branches. In particular, the paper by Boube et al(1) demonstrates a role for PS integrins in promoting migration of a specific tracheal branch.

Animals↗
PubMed1992

Regulation of T cell proliferation by anti-CD49d and anti-CD29 monoclonal antibodies.

The beta 1 integrin VLA-4 (alpha 4 beta 1, CD49d/CD29), which is expressed on a large subpopulation of peripheral blood T lymphocytes, functions as a receptor for the endothelial adhesion protein VCAM-1 and the extracellular matrix protein fibronectin. Previous studies showed that immobilized fibronectin enhanced anti-CD3 monoclonal antibody (mAb)-induced T cell proliferation through binding to the integrins VLA-4 and VLA-5 (alpha 5 beta 1, CD49e/CD29). We studied the ability of the anti-CD49d mAb L25 to potentiate proliferation. T cell proliferation was induced by subthreshold concentrations of anti-CD3 mAb (mAb OKT3) coimmobilized with mAb L25 but not with coimmobilized anti-CD29 (beta 1) mAb. Soluble anti-CD29 mAb inhibited the proliferation induced by coimmobilized mAb OKT3 and L25 but not proliferation induced by mAb OKT3 with PMA or coimmobilized anti-CD26 mAb.

Antigens, CD↗
PubMed2003

Myopodia (postsynaptic filopodia) participate in synaptic target recognition.

Synaptic partner cells recognize one another by utilizing a variety of molecular cues. Prior to neuromuscular synapse formation, Drosophila embryonic muscles extend dynamic actin-based filopodia called "myopodia." In wild-type animals, myopodia are initially extended randomly from the muscle surface but become gradually restricted to the site of motoneuron innervation, a spatial redistribution we call "clustering." Previous experiments with prospero mutant embryos demonstrated that myopodia clustering does not occur in the absence of motoneuron outgrowth into the muscle field. However, whether myopodia clustering is due to a general signal from passing axons or is a result of the specific interactions between synaptic partners remained to be investigated. Here, we have examined the relationship of myopodia to the specific events of synaptic target recognition, the stable adhesion of synaptic partners. We manipulated the embryonic expression of alphaPS2 integrin and Toll, molecules known to affect synaptic development, to specifically alter synaptic targeting on identified muscles. Then, we used a vital single-cell labeling approach to visualize the behavior of myopodia in these animals. We demonstrate a strong positive correlation between myopodia activity and synaptic target recognition. The frequency of myopodia clustering is lowered in cases where synaptic targeting is disrupted. Myopodia clustering seems to result from the adherence of a subset of myopodia to the innervating growth cone while the rest are eliminated. The data suggest that postsynaptic cells play a dynamic role in the process of synaptic target recognition.

Amino Acids↗
PubMed2006

Two types of transmembrane homomeric interactions in the integrin receptor family are evolutionarily conserved.

Integrins are heterodimers, but recent in vitro and in vivo experiments suggest that they are also able to associate through their transmembrane domains to form homomeric interactions. Two fundamental questions are the biological relevance of these aggregates and their form of interaction in the membrane domain. Although in vitro experiments have shown the involvement of a GxxxG-like motif, several crosslinking in vivo data are consistent with an almost opposite form of interaction between the transmembrane alpha-helices. In the present work, we have explored these two questions using molecular dynamics simulations for all available integrin types. We have tested the hypothesis that homomeric interactions are evolutionary conserved, and essential for the cell, using conservative substitutions to filter out nonnative interactions. Our results show that two models, one involving a GxxxG-like motif (model I) and an almost opposite form of interaction (model II) are conserved across all alpha and beta integrin types, both in homodimers and homotrimers, with different specificities. No conserved interaction was found for homotetramers. Our results are completely independent from experimental data, both during molecular dynamics simulations and in the selection of the correct models. We rationalize previous seemingly conflicting findings regarding the nature of integrin interhelical homomeric interactions.

Amino Acid Motifs↗
PubMed1993

Detection of electrophoretic variants of Notch, PS integrin, and DROP-1 proteins in Drosophila following extraction in guanidine hydrochloride.

A method is presented for the rapid extraction of proteins from Drosophila tissues. This method involves lysis of embryos in high concentrations of guanidine hydrochloride, followed by ultracentrifugation in a guanidine hydrochloride step gradient. Several membrane-associated antigens, including Notch and the beta subunit of PS integrin are enriched in this preparation. The quantity of the proteoglycan, DROP-1, obtained from Drosophila eggs and testes was also greatly improved by the guanidine hydrochloride extraction method. This method should prove useful in the isolation and characterization of many Drosophila antigens, particularly those associated with cell membranes.

Animals↗
PubMed2000

Cloning and characterization of alphaP integrin in embryos of the sea urchin Strongylocentrotus purpuratus.

Differentially expressed integrins have been shown to be involved in the intricate cell movements that occur during early development. Because the migration and movement of cells have been well characterized in sea urchin embryos, we searched for alpha-integrin subunits in this organism. An alpha integrin subunit, alphaP, was cloned from Strongylocentrotus purpuratus mesenchyme blastula stage mRNA by RT-PCR and RACE and found to exhibit 74-77% sequence similarity to mammalian alpha(5), alpha(8), alpha(IIb), and alpha(v) integrin. The 8-kb transcript was most abundant at the prism stage, although low levels could be detected at all stages by Northern blot analysis and RT-PCR. A polyclonal antibody to this novel integrin was generated against a 100-amino-acid alphaP fragment fused to glutathione S-transferase and shown to recognize a 180-kDa alpha-integrin in the egg and in all stages of embryogenesis studied.

Amino Acid Sequence↗
PubMed2000

Characterization of gammadelta T cells expressing CD158b, a killer cell inhibitory receptor, in a patient with chronic CD4(+) lymphocytopenia and disseminated Mycobacterium intracellulare infection.

A population of Vdelta1(+)Vgamma9(-) gammadelta T cells that represented almost the totality (84%) of circulating lymphocytes in a patient with chronic, non-HIV-related, CD4 lymphocytopenia complicated by a disseminated Mycobacterium intracellulare infection was characterized. These gammadelta(+) T cells expressed a single killer inhibitory receptor (CD158b) and their phenotype (CD8(+)CD57(+)CD27(-)CD28(-)) indicated that, although CD45RA(+), they were not naive. However, the absence of large granular lymphocyte morphology, the impaired proliferative activity, the high susceptibility to apoptosis, and the total lack of cytotoxic ability suggested that these gammadelta cells were in a resting state. A high percentage of the cells did not harbor the CD11b integrin alpha chain and exhibited a decreased capability to bind endothelial cells. This defect might represent the mechanism whereby they remained trapped in the circulation.

Antigens, CD↗
PubMed2002

Alteration in expression of beta 2 integrins on lamina propria lymphocytes in ulcerative colitis and Crohn's disease.

We have previously demonstrated by immunohistochemistry that mucosal expression of beta 2 integrins was enhanced in Crohn's disease and ulcerative colitis as compared to normal controls. We aimed, therefore, to determine whether there was a corresponding alteration in the expression of CD11a/CD18 (LFA-1), the primary lymphocyte beta 2 integrin, among the principal subsets of lamina propria lymphocytes (LPLs). Accordingly, LPLs were extracted from surgical resection specimens derived from patients with Crohn's colitis, ulcerative colitis, and from noninflamed controls. Following immunofluorescent staining, three-color flow-cytometry analysis identified LPLs on the basis of CD45 side scatter gating, which in turn, were further subdivided into CD4(+), CD8(+), and CD19(+) cells to account for the predominant T and B cells in the lamina propria. Expression patterns of CD11a, the alpha-subunit of LFA-1; CD18, the beta-subunit of LFA-1; and alpha d, a novel alpha-subunit of the beta 2 integrin family were assessed for each of these lymphocyte subsets. In Crohn's disease and ulcerative colitis there was an increased mean percentage expression of CD4(+) cells and CD11a(+) cells compared with noninflamed controls. CD11a was more likely to be expressed on CD4(+) cells in both Crohn's disease and ulcerative colitis and compared with controls and less expressed on CD19(+) cells. It is likely that an influx of CD4(+)11a(+) cells into the lamina propria accounted for these changes. These results suggest that although currently there is great interest in harnessing alpha 4 beta 7 in treatment of inflammatory bowel disease, further consideration should be given to the role of CD11a in these disease states.

Antigens, CD19↗
PubMed1993

PS2 integrin requirements in Drosophila embryo and wing morphogenesis.

The Drosophila inflated (if) gene encodes the alpha PS2 subunit of the PS integrins. We describe the generation of new if mutations, their lethal embryonic phenotype, and experiments that examine the spatial and temporal requirements for integrins in adult wing morphogenesis. Embryos hemizygous for either new allele, ifA7 or ifB2, make reduced amounts of alpha PS2. In a variety of genetic tests, these alleles behave similarly to ifk27e, which makes no detectable alpha PS2, and all three alleles display the same embryonic phenotype. We therefore conclude that all of the lethal alleles retain little or no wild-type alpha PS2 function. As seen for strong mutations at the myospheroid (mys) locus, which encodes the beta PS integrin subunit, if mutants show extreme defects in somatic muscle attachments and in midgut morphogenesis. Unlike mys, however, there is no dorsal herniation of the if mutant embryos. With respect to wing morphogenesis, clonal analysis experiments demonstrate that if+ function is required only in cells of the ventral wing surface. We have rescued the wing blister phenotype of double mutants for the hypomorphic mysnj42 and if3 alleles using a heat shock-inducible mys+ transgene. By varying times of transgene induction, we find that integrin function is required from very early in metamorphosis until at least the last 24-48 hr of wing development.

Alleles↗
PubMed1995

Functions for PS integrins in tissue adhesion, migration, and shape changes during early embryonic development in Drosophila.

The position-specific (PS) integrins of Drosophila are a family of cell surface heterodimers that function as receptors for extracellular matrix molecules. In this study we used time-lapse videomicroscopy to examine living embryos lacking both maternal and zygotic expression of the genes that encode the alpha PS1, alpha PS2, and beta PS integrin subunits. We demonstrate roles for these molecules as early as gastrulation. Abnormalities in mutant embryos include: separation and twisting of the embryonic germband, abnormal shape and migration of midgut primordia, irregular visceral mesoderm, detachment of amnioserosa cells, rupture of the cuticle along the dorsal midline, lack of midgut constriction, and detachment of somatic muscles. These observations suggest multiple roles for PS integrins in the adhesion of cells and in the formation, organization, and migration of embryonic tissues. We also show that although alpha PS1 beta PS and alpha PS2 beta PS are often expressed in adjacent embryonic tissues, this distribution does not necessarily reflect equivalent requirements. Furthermore, the complete loss of both alpha subunits does not produce all of the phenotypes observed in embryos lacking beta PS. This suggests that alpha PS1 beta PS and alpha PS2 beta PS are not required in all embryonic processes utilizing PS integrins.

Animals↗
PubMed1996

Development of the indirect flight muscle attachment sites in Drosophila: role of the PS integrins and the stripe gene.

Using markers that are expressed at muscle attachment sites, we have examined the early pupal development (first 36 hr) of Indirect Flight Muscle (IFM) attachments in the fruit fly Drosophila melanogaster. Expression of the Drosophila homologs of vertebrate integrins, the Position-Specific (PS) antigens, is known to differentially mark epidermal (PS1alpha) and muscle (PS2alpha) components of the developing IFM attachment sites. During myogenesis, PS2alpha is detected transiently in imaginal myoblasts that fuse with persistent larval muscles to give rise to the Dorsal Longitudinal Muscles (DLMs), but not in myoblasts that fuse de novo to give rise to the Dorso Ventral Muscles. The integrins are not expressed at attachment sites when the muscle fibers first make their appearance (12-20 hr). Following muscle-epidermal contact, PS1 and PS2 are detected at muscle attachment sites. PS1 expression is at the muscle ends and also in the long epidermal processes that connect the developing muscle fibers to their sites of attachment in the epidermis, while PS2 expression is restricted to the muscle ends. Epidermal cells that will contribute to the adult attachment sites are defined as early as the third larval instar. Both anterior and posterior sites of attachment of the IFMs are marked by the expression of reporter beta-galactosidase activity in a P-element line B14.0, which is an insertion at the stripe locus. B14.0 (stripe) is seen in distinct domains in the wing and leg imaginal discs which give rise to the thoracic cuticle. The expression is maintained during pupal development. The B14.0 (stripe) expressing epidermal cells contact the developing muscle fibers, leading to the formation of the myotendon junction. We show that the dorsal and ventral attachment sites of one group of IFMs, the DVMs arise from two different imaginal discs (wing and leg, respectively), which may explain the differential effect of mutations such as bendless on these muscles. Attachment sites for the other group of IFMs, the DLMs, on the other hand, arise from one imaginal disc (wing). B14.0 (stripe) expression defines epidermal cells of the adult attachment sites and is likely to function during early events leading to the formation of muscle-epithelial contacts. The PS integrins are detected at later stages, suggesting a role in the stabilization and maturation of the muscle-epidermal contacts into myotendon junctions.

Animals↗
PubMed1998

Absence of PS integrins or laminin A affects extracellular adhesion, but not intracellular assembly, of hemiadherens and neuromuscular junctions in Drosophila embryos.

We have examined the role of integrins in the formation of the cell junctions that connect muscles to epidermis (muscle attachments) and muscles to neurons (neuromuscular junctions). To this end we have analyzed muscle attachments and neuromuscular junctions ultrastructurally in single or double mutant Drosophila embryos lacking PS1 integrin (alphaPS1betaPS), PS2 integrin (alphaPS2betaPS), and/or their potential extracellular ligand laminin A. At the muscle attachments PS integrins are essential for the adhesion of hemiadherens junctions (HAJs) to extracellular matrix, but not for their intracellular link to the cytoskeleton. The PS2 integrin is only expressed in the muscles, but it is essential for the adhesion of muscle and epidermal HAJs to electron dense extracellular matrix. It is also required for adhesion of muscle HAJs to a less electron dense form of extracellular matrix, the basement membrane. The PS1 integrin is expressed in epidermal cells and can mediate adhesion of the epidermal HAJs to the basement membrane. The ligands involved in adhesion mediated by both PS integrins seem distinct because adhesion mediated by PS1 appears to require the extracellular matrix component laminin A, while adhesion mediated by PS2 integrin does not. At neuromuscular junctions the formation of functional synapses occurs normally in embryos lacking PS integrins and/or laminin A, but the extent of contact between neuronal and muscle surfaces is altered significantly. We suggest that neuromuscular contact in part requires basement membrane adhesion to the general muscle surface, and this form of adhesion is completely abolished in the absence of laminin A.

Animals↗
PubMed2001

Laminin-induced change in conformation of preexisting alpha7beta1 integrin signals secondary myofiber formation.

Two distinct populations of myoblasts, distinguishable by alpha7 integrin expression have been hypothesized to give rise to two phases of myofiber formation in embryonic limb development. We show here that alpha7 integrin is detectable far earlier than previously reported on both "primary" and "secondary" lineage myoblasts and myofibers. An antibody (1211) that recognizes an intracellular epitope allowed detection of alpha7 integrin previously missed using an antibody (H36) that recognizes an extracellular epitope. We found that when myoblasts were isolated and cultured from different developmental stages, H36 only detected alpha7 integrin that was in direct contact with its ligand, laminin. Moreover, alpha7 integrin detection by H36 was reversible and highly localized to subcellular points of contact between myoblasts and laminin-coated 2.8-microm microspheres. Prior to secondary myofiber formation in limb embryogenesis, laminin was present but not in close proximity to clusters of primary myofibers that expressed alpha7 integrin detected by antibody 1211 using deconvolution microscopy. These results suggest that the timing of the interaction of preexisting alpha7 integrin with its ligand, laminin, is a major determinant of allosteric changes that result in an activated form of alpha7 integrin capable of transducing signals from the extracellular matrix commensurate with secondary myofiber formation.

Animals↗
PubMed2001

alpha11beta1 integrin is a receptor for interstitial collagens involved in cell migration and collagen reorganization on mesenchymal nonmuscle cells.

alpha11beta1 integrin constitutes a recent addition to the integrin family. Here, we present the first in vivo analysis of alpha11 protein and mRNA distribution during human embryonic development. alpha11 protein and mRNA were present in various mesenchymal cells around the cartilage anlage in the developing skeleton in a pattern similar to that described for the transcription factor scleraxis. alpha11 was also expressed by mesenchymal cells in intervertebral discs and in keratocytes in cornea, two sites with highly organized collagen networks. Neither alpha11 mRNA nor alpha11 protein could be detected in myogenic cells in human embryos. The described expression pattern is compatible with alpha11beta1 functioning as a receptor for interstitial collagens in vivo. To test this hypothesis in vitro, full-length human alpha11 cDNA was stably transfected into the mouse satellite cell line C2C12, lacking endogenous collagen receptors. alpha11beta1 mediated cell adhesion to collagens I and IV (with a preference for collagen I) and formed focal contacts on collagens. In addition, alpha11beta1 mediated contraction of fibrillar collagen gels in a manner similar to alpha2beta1, and supported migration on collagen I in response to chemotactic stimuli. Our data support a role for alpha11beta1 as a receptor for interstitial collagens on mesenchymally derived cells and suggest a multifunctional role of alpha11beta1 in the recognition and organization of interstitial collagen matrices during development.

Animals↗