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PubMed2002

Antioxidant potential and gap junction-mediated intercellular communication as early biological markers of mercuric chloride toxicity in the MDCK cell line.

In this study, the early nephrotoxic potential of mercuric chloride (HgCl(2)) has been evaluated in vitro, by exposing a renal-derived cell system, the tubular epithelial Madin-Darby canine kidney (MDCK) cell line, to the presence of increasing HgCl(2) concentrations (0.1-100 microM) for different periods of time (from 4 to 72 h). As possible biological markers of the tubular-specific toxicity of HgCl(2) in exposed-MDCK cultures we analysed: (i) critical biochemical parameters related to oxidative stress conditions and (ii) gap-junctional function (GJIC). HgCl(2) cytotoxicity was evaluated by cell-density assay. The biochemical analysis of the pro-oxidant properties of the mercuric ion (Hg(2+)) was performed by evaluating the effect of the metal salt on the antioxidant status of the MDCK cells. The cell glutathione (GSH) content and the activity of glutathione peroxidase (Gpx) and catalase (Cat), two enzymes engaged in the H(2)O(2) degradation, were quantified. HgCl(2) influence on MDCK GJIC was analysed by the microinjection/dye-transfer assay. HgCl(2)-induced morphological changes in MDCK cells were also taken into account. Our results, proving that subcytotoxic (0.1-10 microM) HgCl(2) concentrations affect either the antioxidant defences of MDCK cells or their GJIC, indicate these critical functions as suitable biological targets of early mercury-induced tubular cell injury.

Animals↗
PubMed2005

Connexins and their channels in cell growth and cell death.

Direct communication between cells, mediated by gap junctions, is nowadays considered as an indispensable mechanism in the maintenance of cellular homeostasis. In fact, gap junctional intercellular communication is actively involved in virtually all aspects of the cellular life cycle, ranging from cell growth to cell death. For a long time, it was believed that this was merely a result of the capacity of gap junctions to control the direct intercellular exchange of essential cellular messengers. However, recent data show that the picture is more complicated than initially thought, as structural precursors of gap junctions, connexins and gap junction hemichannels, can affect the cellular homeostatic balance independently of gap junctional intercellular communication. In this paper, we summarize the current knowledge concerning the roles of connexins and their channels in the control of cellular homeostasis, with the emphasis on cell growth and cell death. We also briefly discuss the role of gap junctional intercellular communication in carcinogenesis and the potential use of connexins as tools for cancer therapy.

Animals↗
PubMed2006

The influence of lycopene on the proliferation of human breast cell line (MCF-7).

Lycopene, a non-provitaminic carotenoid, present in many fruit and vegetables, such as tomatoes and their processed products, has been associated with decreased risk of chronic diseases including cancer. The influence of lycopene on the proliferation of the breast tumour cell line (MCF-7) was tested using MTT and BrdU assays at different time intervals (from 24 to 72h) and dose-response (from 0.125 to 100microM). The induction of Gap Junction Intercellular Communication (GJIC) was evaluated by dye-transfer assay using Lucifer Yellow on monolayer cells treated with different lycopene concentrations (from 0.125 to 5microM) for 6 to 48h. The Minimal Inhibitory Concentration (MIC) of lycopene was of 5microM, after a 24h exposure. A prolonged exposure time (72h) induced a similar inhibitory effect. Lycopene stimulated the functionality of GJIC at concentrations of 1microM after 24h and this effect was dose-dependent. The induction of GJIC by lycopene was confirmed by an increased expression of connexin 43. Collectively, the above data confirm the inhibitor effects of lycopene on MCF-7 cell growth and suggest that lycopene is involved in the modulation of the gap junction intercellular communication in this cell line, as observed for other cancer cell lines.

Anticarcinogenic Agents↗
PubMed1984

Epithelial cytoskeletal framework and nuclear matrix-intermediate filament scaffold: three-dimensional organization and protein composition.

Madin-Darby canine kidney (MDCK) cells grow as differentiated, epithelial colonies that display tissue-like organization. We examined the structural elements underlying the colony morphology in situ using three consecutive extractions that produce well-defined fractions for both microscopy and biochemical analysis. First, soluble proteins and phospholipid were removed with Triton X-100 in a physiological buffer. The resulting skeletal framework retained nuclei, dense cytoplasmic filament networks, intercellular junctional complexes, and apical microvillar structures. Scanning electron microscopy showed that the apical cell morphology is largely unaltered by detergent extraction. Residual desmosomes, as can be seen in thin sections, were also well-preserved. The skeletal framework was visualized in three dimensions as an unembedded whole mount that revealed the filament networks that were masked in Epon-embedded thin sections of the same preparation. The topography of cytoskeletal filaments was relatively constant throughout the epithelial sheet, particularly across intercellular borders. This ordering of epithelial skeletal filaments across contiguous cell boundaries was in sharp contrast to the more independent organization of networks in autonomous cells such as fibroblasts. Further extraction removed the proteins of the salt-labile cytoskeleton and the chromatin as separate fractions, and left the nuclear matrix-intermediate filament (NM-IF) scaffold. The NM-IF contained only 5% of total cellular protein, but whole mount transmission electron microscopy and immunofluorescence showed that this scaffold was organized as in the intact epithelium. Immunoblots demonstrate that vimentin, cytokeratins, desmosomal proteins, and a 52,000-mol-wt nuclear matrix protein were found almost exclusively in the NM-IF scaffold. Vimentin was largely perinuclear while the cytokeratins were localized at the cell borders. The 52,000-mol-wt nuclear matrix protein was confined to the chromatin-depleted matrix and the desmosomal proteins were observed in punctate polygonal arrays at intercellular junctions. The filaments of the NM-IF were seen to be interconnected, via the desmosomes, over the entire epithelial colony. The differentiated epithelial morphology was reflected in both the cytoskeletal framework and the NM-IF scaffold.

Animals↗
PubMed2004

An endothelial and astrocyte co-culture model of the blood-brain barrier utilizing an ultra-thin, nanofabricated silicon nitride membrane.

The endothelial cells comprising brain capillaries have extremely tight intercellular junctions which form an essentially impermeable barrier to passive transport of water soluble molecules between the blood and brain. Several in vitro models of the blood-brain barrier (BBB) have been studied, most utilizing commercially available polymer membranes affixed to plastic inserts. There is mounting evidence that direct contact between endothelial cells and astrocytes, another cell type found to have intimate interaction with the brain side of BBB capillaries, is at least partially responsible for the development of the tight intercellular junctions between BBB endothelial cells. However, the membranes commonly used for BBB in vitro models are lacking certain attributes that would permit a high degree of direct contact between astrocytes and endothelial cells cultured on opposing sides. This work is based on the hypothesis that co-culturing endothelial and astrocyte cells on opposite sides of an ultra-thin, highly porous membrane will allow for increased direct interaction between the two cell types and therefore result in a better model of the BBB. We used standard nanofabrication techniques to make membranes from low-stress silicon nitride that are at least an order of magnitude thinner and at least two times more porous than commercial membrane inserts. An experimental survey of pore sizes for the silicon nitride membranes suggested pores approximately 400 nm in diameter are adequate for restricting astrocyte cell bodies to the seeded side while allowing astrocyte processes to pass through the pores and interact with endothelial cells on the opposite side. The inclusion of a spun-on, cross-linked collagen membrane allowed for astrocyte attachment and culture on the membranes for over two weeks. Astrocytes and endothelial cells displayed markers specific to their cell types when grown on the silicon nitride membranes. The transendothelial electrical resistances, a measure of barrier tightness, of endothelial and astrocyte co-cultures on the silicon nitride membranes were comparable to the commercial membranes, but neither system showed synergy between the two cell types in forming a tighter barrier. This lack of synergy may have been due to the loss of ability of commercially available primary bovine brain microvascular endothelial cells to respond to astrocyte differentiating signals.

Animals↗
PubMed2002

CAS/CSE 1 stimulates E-cadhrin-dependent cell polarity in HT-29 human colon epithelial cells.

The establishment and maintenance of epithelial polarity are crucial for tissue organization and function in mammals. Epithelial cadherin (E-cadherin) is expressed in epithelial cell membrane and is important for cell-cell adhesion, intercellular junctions formation, as well as epithelial cell polarization. We report herein that CAS (CAS/CSE 1), the human cellular apoptosis susceptibility protein, interacts with E-cadherin and stimulates polarization of HT-29 human colon epithelial cells. CAS binds with E-cadherin but not with beta-catenin in the immunoprecipitation assays. Interaction of CAS with E-cadherin enhances the formation of E-cadherin/beta-catenin cell-cell adhesive complex. Electron microscopic study demonstrated that CAS overexpression in cells stimulates intercellular junction complex formation. The disorganization of cellular cytoskeleton by cytochalasin D, colchicine, or acrylamide treatment disrupts CAS-stimulated HT-29 cell polarization. CAS-mediated HT-29 cell polarity is also inhibited by antisense E-cadherin DNA expression. Our results indicate that CAS cooperates with E-cadherin and plays a role in the establishment of epithelial cell polarity.

Acrylamide↗
PubMed1995

Expression and in vitro regulation of integrins by normal human urothelial cells.

Integrins are thought to be essential adhesion receptors for the maintenance of tissue histioarchitecture. The purpose of this study was to determine integrin expression patterns in the human stratified transitional epithelium of the urinary tract (urothelium). In situ expression patterns were compared with in vitro expression, using a normal cell culture model system in which the effects of cell stratification can be studied independently of differentiation. By immunohistological criteria, the urothelia of bladder, ureter and renal pelvis expressed alpha 2 beta 1 and alpha 3 beta 1 integrins in all layers at intercellular junctions, and cytoplasmically in the lower strata. By contrast, alpha 6 beta 4 and occasionally alpha v beta 4 were expressed only by basal cells and localised to the basal lamina. These expression patterns were unaltered in specimens where an inflammatory cell infiltrate was present. In long-term cultures of normal urothelial cells maintained in a low-Ca++ serum-free medium, the monolayer cultures expressed alpha 2 beta 1, alpha 3 beta 1 and alpha 5 beta 1 integrins at intercellular junctions and in cytoplasmic inclusions, whereas alpha 6 beta 4 was distributed in a random pattern over the substratum. Increasing exogenous Ca++ concentrations induced cell stratification and desmosome formation, but not cytodifferentiation. Under these conditions, alpha 6 beta 4 became cell-, rather than substratum-associated, localising particularly to filopodia and lamellipodia. Quantitation of integrin expression by flow cytometry confirmed increased surface expression of alpha 6 beta 4 in high Ca++ media, and also of alpha 3 and alpha 5, but not alpha 2, subunits. These results suggest that alpha 2 beta 1 and alpha 3 beta 1 integrins, although differentially regulated, are mainly involved in homotypic cell-cell interactions and the maintenance of a stratified morphology, whereas alpha 6 beta 4 is the principal integrin involved in substratum adhesion.

Adolescent↗
PubMed1992

Ultrastructural alterations in mouse capillary blood vessels after experimental injection of venom from the snake Bothrops asper (Terciopelo).

Histological and ultrastructural alterations in capillary blood vessels were studied at various time intervals after im injection of 50 micrograms of Bothrops asper snake venom in mouse gastrocnemius muscle. Hemorrhage was observed as early as 5 min after envenomation, as abundant erythrocytes appeared in the interstitial space. Ultrastructural observations revealed two different patterns of pathological changes: in the majority of damaged capillaries, endothelial cells had blebs and cytoplasmic projections pinching off to the lumen. This phenomenon was observed together with a decrease in the number of pinocytotic vesicles, with endothelial cells becoming very thin. As an apparent consequence of this process, some endothelial cells had evident gaps in their continuity. In addition, basal laminae surrounding these capillaries were altered and discontinuous. Other endothelial cells underwent a morphologically different process of degeneration, characterized by swelling of the endoplasmic reticulum and of the cytosol. These cells had a diffuse appearance and their basal laminae were discontinuous or absent. No major changes in the intercellular junctions were noticed in damaged endothelial cells. Samples obtained 30 and 60 min after venom injection were devoid of normal capillaries in many areas, and only diffuse remnants of their structure were found. Many altered capillaries had platelet aggregates and fibrin, the latter also being observed in the interstitial space. It is concluded that B. asper venom induces rapid and drastic pathological effects on capillaries leading to hemorrhage per rhexis i.e., erythrocytes probably escape through gaps in damaged endothelial cells and not through widened intercellular junctions.

Animals↗
PubMed1980

[Physiological importance of gap junctions].

Some structural features of the different types of intercellular junctions which occur in vertebrate tissues (desmosomes, tight and gap junctions, Table 1) are first mentioned. Then, this review is exclusively concerned with gap junctions. The ubiquitous occurrence of these junctions throughout the phylogenetic scale up to man points to a major functional role. Cells of most organized tissues make cell-to-cell channels, 1-2 nm diameter, that provide a structural hydrophilic pathway for free diffusion of inorganic ions and small molecules. Ionic coupling and metabolic cooperation have been shown to be functional expressions of the direct intercellular communication. The role of gap junctions in nonexcitable tissues is not well established (Chap. III). While these junctions are clearly involved in the regulation of some enzymatic activities and exocrine and endocrine secretions, the cell-to-cell transmission of signal molecules necessary for growth control remains largely hypothetical.

Animals↗
PubMed1979

Regional differences in the fine structure of the ciliary epithelium related to accommodation.

The ciliary bodies of five monkey eyes and one human eye were subdivided into five zones. The ciliary epithelium with its bordering stroma was investigated electron microscopically. The number of cell organelles of the nonpigmented (NPE) and pigmented (PE) epithelium (mitochondria, rough endoplasmic reticulum, Golgi complexes); intercellular junctions between NPE and NPE, PE and PE, and NPE and PE (desmosomes, puncta adhaerentia, gap junctions, tight junctions); and fenestrations of the capillary endothelium were quantitatively evaluated. All these types of cell organelles, fenestrations of the capillary endothelium, and gap junctions in the NPE were found in greater numbers at the crests of the ciliary processes than in the valleys between processes. On the other hand, the number of puncta adhaerentia is significantly higher in the valleys than at the crests. In the valleys, the internal limiting membrane performs an elaborate network of electron-dense strands in which many fine zonular fibers terminate. These fibers are believed to belong to the "tension fiber system." Their firm attachment to the ciliary epithelium and the great number of intercellular junctions known as mechanical structures lend further support to our concept that these structures function as a fulcrum in the process of accommodation.

Accommodation, Ocular↗
PubMed2001

Free radical-initiated and gap junction-mediated bystander effect due to nonuniform distribution of incorporated radioactivity in a three-dimensional tissue culture model.

To investigate the biological effects of nonuniform distribution of radioactivity in mammalian cells, we have developed a novel three-dimensional tissue culture model. Chinese hamster V79 cells were labeled with tritiated thymidine and mixed with unlabeled cells, and multicellular clusters (approximately 1.6 mm in diameter) were formed by gentle centrifugation. The short-range beta particles emitted by (3)H impart only self-irradiation of labeled cells without significant cross-irradiation of unlabeled bystander cells. The clusters were assembled in the absence or presence of 10% dimethyl sulfoxide (DMSO) and/or 100 microM lindane. DMSO is a hydroxyl radical scavenger, whereas lindane is an inhibitor of gap junctional intercellular communication. The clusters were maintained at 10.5 degrees C for 72 h to allow (3)H decays to accumulate and then dismantled, and the cells were plated for colony formation. When 100% of the cells were labeled, the surviving fraction was exponentially dependent on the mean level of radioactivity per labeled cell. A two-component exponential response was observed when either 50 or 10% of the cells were labeled. Though both DMSO and lindane significantly protected the unlabeled or bystander cells when 50 or 10% of the cells were labeled, the effect of lindane was greater than that of DMSO. In both cases, the combined treatment (DMSO + lindane) elicited maximum protection of the bystander cells. These results suggest that the bystander effects caused by nonuniform distributions of radioactivity are affected by the fraction of cells that are labeled. Furthermore, at least a part of these bystander effects are initiated by free radicals and are likely to be mediated by gap junctional intercellular communication.

Animals↗
PubMed2000

Regulation of intercellular tight junctions by zonula occludens toxin and its eukaryotic analogue zonulin.

The intestinal epithelium represents the largest interface between the external environment and the internal host milieu and constitutes the major barrier through which molecules can either be absorbed or secreted. There is now substantial evidence that tight junctions (tj) play a major role in regulating epithelial permeability by influencing paracellular flow of fluid and solutes. Tj are one of the hallmarks of absorptive and secretory epithelia. Evidence now exists that tj are dynamic rather than static structures and readily adapt to a variety of developmental, physiological, and pathological circumstances. These adaptive mechanisms are still incompletely understood. Activation of PKC either by Zonula occludens toxin (Zot) or by phorbol esters increases paracellular permeability. Alteration of epithelial tj is a recently described property for infectious agents. Clostridium difficile toxin A and B and influenza and vesicular stomatitis viruses have been shown to loosen tj in tissue culture monolayers. Unlike what occurs after the Zot stimulus, these changes appear to be irreversible and are associated with destruction of the tj complex. On the basis of this observation, we postulated that Zot may mimic the effect of a functionally and immunologically related endogenous modulator of epithelial tj. We were able to identify an intestinal Zot analogue, which we named zonulin. It is conceivable that the zonulins participate in the physiological regulation of intercellular tj not only in the small intestine, but also throughout a wide range of extraintestinal epithelia as well as the ubiquitous vascular endothelium, including the blood-brain barrier. Disregulation of this hypothetical zonulin model may contribute to disease states that involve disordered intercellular communication, including developmental and intestinal disorders, tissue inflammation, malignant transformation, and metastasis.

Cholera Toxin↗
PubMed2001

Studies on in vitro evaluation for the biocompatibility of various biomaterials: inhibitory activity of various kinds of polymer microspheres on metabolic cooperation.

Gap junctional intercellular communication is a function that plays an important role in maintaining cell and tissue homeostasis and in regulating cell growth, development, and differentiation. Change in this function when contacting fibroblasts with various polymer microspheres was estimated using the metabolic cooperation assay system. When the cells were in contact with the microspheres after their adhesion onto a substrate, the function did not alter. However, when they were in contact with precoated microspheres on test dishes, the function was inhibited as the quantity of microspheres increased. Moreover, the inhibition level increased as the diameters of polyethylene and polystyrene microspheres decreased. However, no inhibition was observed if precoated microspheres were composed from poly(L-lactic acid). These findings suggest that the size and the material of microspheres, and how cells recognize the microspheres, are factors affecting cell function of gap junctional intercellular communication. Therefore, estimating this function may provide valuable information about the biocompatibility of many kinds of materials even in the form of particles.

Animals↗
PubMed1996

CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins.

Neurexins are neuronal cell surface proteins with hundreds of isoforms. In yeast two-hybrid screens for intracellular molecules interacting with different neurexins, we identified a single interacting protein called CASK. CASK is composed of an N-terminal Ca2+, calmodulin-dependent protein kinase sequence and a C-terminal region that is similar to the intercellular junction proteins dlg-A, PSD95/SAP90, SAP97, Z01, and Z02 and that contains DHR-, SH3-, and guanylate kinase domains. CASK is enriched in brain in synaptic plasma membranes but is also detectable at low levels in all tissues tested. The cytoplasmic domains of all three neurexins bind CASK in a salt-labile interaction. In neurexin I, this interaction is dependent on the C-terminal three residues. Thus, CASK is a membrane-associated protein that combines domains found in Ca2+ - activated protein kinases and in proteins specific for intercellular junctions, suggesting that it may be a signaling molecule operating at the plasma membrane, possibly in conjunction with neurexins.

Animals↗
PubMed2005

Ultrastructural changes in rat livers perfused in vitro and in vivo with a high dose of methotrexate.

Methotrexate is an antifolate that is widely used in the treatment of malignant tumours and other diseases. The present study was undertaken to examine the short-term effects of high doses of methotrexate (HD-MTX) on the ultrastructure and metabolic activity of isolated rat livers. The authenticity of the drug-induced changes was substantiated by the concomitant use of in vivo experiments. Isolated rat livers were infused with HD-MTX via the portal vein for 3 hours (total dose for each liver 2000 mg). For in vivo experiments, each rat received a single intravenous injection of a maximum tolerated dose of MTX (100 mg/kg body weight) that allowed the animals to survive for 3 days. At the end of each experimental period, MTX-treated and control livers were processed for light microscopy (LM), scanning (SEM) and transmission electron (TEM) microscopy. Oxygen consumption and thyroxine metabolism were measured in treated and control isolated livers. With the exception of a few minor differences, the structural changes in the hepatocytes after MTX treatment in vitro and vivo were similar. There were focal changes consisting of disruption of normal hepatic plates and swelling and vacuolation of the hepatocytes, with no clear evidence of restriction to a specific hepatic zone. SEM revealed striking changes in the plasma membrane, the microvillar system, intercellular junctions and the sinusoidal endothelium. TEM revealed disorganized endoplasmic reticulum, dispersion of the polyribosomes, a variety of mitochondrial changes, and glycogen redistribution. In MTX-treated isolated rat livers, the uptake of tetraiodothyronine (T4) was not affected, but triiodothyronine (T3) release was impaired. Oxygen consumption was increased in livers treated with MTX. Employing an organotypic liver perfusion model in conjunction with the in vivo experiment and the use of SEM, TEM and hepatic thyroxine measurements, this investigation revealed that infusion of HD-MTX induced early ultrastructual changes in cell membrane, intercellular junctions and cell organelles and disturbance in the functional integrity of the hepatocytes in isolated rat liver.

Animals↗
PubMed2006

A novel N14Y mutation in Connexin26 in keratitis-ichthyosis-deafness syndrome: analyses of altered gap junctional communication and molecular structure of N terminus of mutated Connexin26.

Connexins (Cxs) are transmembranous proteins that connect adjacent cells via channels known as gap junctions. The N-terminal 21 amino acids of Cx26 are located at the cytoplasmic side of the channel pore and are thought to be essential for the regulation of channel selectivity. We have found a novel mutation, N14Y, in the N-terminal domain of Cx26 in a case of keratitis-ichthyosis-deafness syndrome. Reduced gap junctional intercellular communication was observed in the patient's keratinocytes by the dye transfer assay using scrape-loading methods. The effect of this mutation on molecular structure was investigated using synthetic N-terminal peptides from both wild-type and mutated Cx26. Two-dimensional (1)H nuclear magnetic resonance and circular dichroism measurements demonstrated that the secondary structures of these two model peptides are similar to each other. However, several novel nuclear Overhauser effect signals appeared in the N14Y mutant, and the secondary structure of the mutant peptide was more susceptible to induction of 2,2,2-trifluoroethanol than wild type. Thus, it is likely that the N14Y mutation induces a change in local structural flexibility of the N-terminal domain, which is important for exerting the activity of the channel function, resulting in impaired gap junctional intercellular communication.

3T3 Cells↗
PubMed1997

Co-ordinated expression of connexins 26 and 32 in human endometrial glandular epithelium during the reproductive cycle and the influence of hormone replacement therapy.

Hormones are involved in the regulation of intercellular communication, and gap junction intercellular communication may play an important role in the prevention of endometrial cancer. We have investigated changes in the expression of the gap junction proteins connexin 26 (Cx26) and Cx32 in human endometrial glandular epithelium during the reproductive cycle as well as the influence of hormone replacement therapy. Frozen sections from 71 endometrial tissue samples (53 taken from women who had undergone hysterectomy during the menstrual cycle, 3 early pregnancy deciduae and 15 from menopausal women, some of whom were receiving estrogen alone or estrogen plus progesterone) were analyzed by immunofluorescence and confocal laser scanning microscopy. Cx26 and Cx32 were expressed weakly in the proliferative phase, markedly during ovulation and most strongly in the mid-secretory phase; by the late secretory phase, they decreased drastically. Cx26 and Cx32 also were expressed in early pregnancy. Women who had received estrogen and progesterone expressed the Cxs, but those who had received estrogen only or no therapy did not. These results were confirmed by Western blot analysis. They indicate that expression of Cx26 and Cx32 is correlated with cell differentiation and with the glandular function of the endometrial epithelium and suggest that expression of Cxs is controlled by serum progesterone.

Blotting, Western↗
PubMed2001

Synaptic pattern formation during cellular recognition.

Cell-cell recognition often requires the formation of a highly organized pattern of receptor proteins (a synapse) in the intercellular junction. Recent experiments [e.g., Monks, C. R. F., Freiberg, B. A., Kupfer, H., Sciaky, N. & Kupfer, A. (1998) Nature (London) 395, 82-86; Grakoui, A., Bromley, S. K., Sumen, C., Davis, M. M., Shaw, A. S., Allen, P. M. & Dustin, M. L. (1999) Science 285, 221-227; and Davis, D. M., Chiu, I., Fassett, M., Cohen, G. B., Mandelboim, O. & Strominger, J. L. (1999) Proc. Natl. Acad. Sci. USA 96, 15062-15067] vividly demonstrate a complex evolution of cell shape and spatial receptor-ligand patterns (several microns in size) in the intercellular junction during immunological synapse formation. The current view is that this dynamic rearrangement of proteins into organized supramolecular activation clusters is driven primarily by active cytoskeletal processes [e.g., Dustin, M. L. & Cooper, J. A. (2000) Nat. Immunol. 1, 23-29; and Wulfing, C. & Davis, M. M. (1998) Science 282, 2266-2269]. Here, aided by a quantitative analysis of the relevant physico-chemical processes, we demonstrate that the essential characteristics of synaptic patterns observed in living cells can result from spontaneous self-assembly processes. Active cellular interventions are superimposed on these self-organizing tendencies and may also serve to regulate the spontaneous processes. We find that the protein binding/dissociation characteristics, protein mobilities, and membrane constraints measured in the cellular environment are delicately balanced such that the length and time scales of spontaneously evolving patterns are in near-quantitative agreement with observations for synapse formation between T cells and supported membranes [Grakoui, A., Bromley, S. K., Sumen, C., Davis, M. M., Shaw, A. S., Allen, P. M. & Dustin, M. L. (1999) Science 285, 221-227]. The model we present provides a common way of analyzing immunological synapse formation in disparate systems (e.g., T cell/antigen-presenting cell junctions with different MHC-peptides, natural killer cells, etc.).

Animals↗