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PubMed2004

Breaking into the epithelial apical-junctional complex--news from pathogen hackers.

The epithelial apical-junctional complex is a key regulator of cellular functions. In addition, it is an important target for microbial pathogens that manipulate the cell to survive, proliferate and sometimes persist within a host. Out of a myriad of potential molecular targets, some bacterial and viral pathogens have selected a subset of protein targets at the apical-junctional complex of epithelial cells. Studying how microbes use these targets also teaches us about the inherent physiological properties of host molecules in the context of normal junctional structure and function. Thus, we have learned that three recently uncovered components of the apical-junctional complex of the Ig superfamily--junctional adhesion molecule, Nectin and the coxsackievirus and adenovirus receptor--are important regulators of junction structure and function and represent critical targets of microbial virulence gene products.

Animals↗

PubMed2006

The effect of 6 months of treatment with pravastatin on serum adiponection concentrations in Japanese patients with coronary artery disease and hypercholesterolemia: a pilot study.

BACKGROUND: Pravastatin has been reported to reduce cardiovascular events and mortality in patients with coronary artery disease (CAD). Hypoadiponectinemia is a known risk factor for CAD. OBJECTIVE: This study analyzed the effects of shortterm pravastatin treatment on serum lipid and adiponectin concentrations in patients with CAD and hypercholesterolemia. METHODS: This was a multicenter, observational pilot study of the effect of 6 months of treatment with pravastatin 10 to 20 mg/d on serum adiponection concentrations in patients with documented CAD and total cholesterol (TC) levels> or =180 mg/dL. Patients from 13 medical centers in Japan were monitored at visits every 4 weeks for assessment of compliance and adverse effects. For the assessment of pravastatin's effects, patients were categorized according to baseline serum adiponectin concentrations: quartile 1 (Q1) = < 4.83 microg/mL; quartile 2 (Q2) = 4.83 to 7.20 microg/mL; (Q4) = > 10.38 microg/mL. The primary end point of the study was the percent change from baseline in adiponectin nectin concentrations at 6 months. Secondary end points were changes in lipids, high-sensitivity C-reactive protein (hsCRP), and glycosylated hemoglobin (HbA1c). RESULTS: One hundred thirty consecutive patients were enrolled; 11 were excluded and 4 discontinued due to adverse events. Thus, 115 patients were included in the study analyses (83 men, 32 women; mean age, 68 years). No patient had a cardiac event during the 6-month follow-up period. After 6 months of pravastatin treatment, 74 (64.3%) patients had increases in serum adiponectin concentrations. Median (interquartile range) adiponectin concentrations increased significantly from 7.2 (4.8-10.4) mug/mL at baseline to 7.8 (5.4-11.2) microg/mL after 6 months of pravastatin treatment (P<0.001); the mean percent increase from baseline was 16.3%. The percent increase from baseline in serum adiponection concentrations was significantly higher among patients in Q1 (39.3%) compared with those in Q3 (4.5%) and Q4 (6.3%) (P<0.003 and P<0.005, respectively). The relative increase in adiponectin concentrations was significantly correlated with the relative increase in high-density lipoprotein cholesterol (HDL-C) (f=0.47; P<0.001). After 6 months of pravastatin treatment, TC and low-density lipoprotein cholesterol levels had decreased, by 14.6% and 23.3%, respectively, and HDL-C levels had increased by 14.0% (all, P<0.001). The change in triglycerides (-13.3%) was not statistically significant. Serum hsCRP levels were significantly decreased from baseline after 6 months of pravastatin treatment (P<0.001). HbA1c did not change significantly. CONCLUSION: In this pilot study in Japanese patients with CAD and hypercholesterolemia, 6 months of treatment with pravastatin 10 to 20mg/d was associated with significant increases in serum adiponectin concentrations.

Adiponectin↗

PubMed2004

Speculations on the origin of the vertebrate immune system.

As one studies more and more the immune systems of invertebrates their multiplicity and diversity increase. On one hand, the number of different local and systemic innate mechanisms (or cascades of mechanisms) increases with every phylum studied, on the other hand the diversity increases within each system as multiple loci and polymorphisms are discovered. Even somatic variation is not restricted to vertebrates. Yet no immune system similar to that of vertebrates characterized by the usage of RAG enzymes, has been found below jawed vertebrates. The availability of genome projects in early chordates allows understanding better the different causal lines that led to the generation of the vertebrate system with its diverse repertoire of antigen receptors generated somatically. This paper singles out a linkage group in human, gathering genes of the Ig superfamily with structural relationships to the antigen receptor JAM/CTX, nectin, or to some haematopoietic cells CD that have homologues in protochordates such as Branchiostoma and Ciona or in more primitive protostomes. The role of virus receptor for many of these clustered genes products provides perhaps one way of envisaging the recruitment of this family in the adaptive immune system from an ancient form of innate antiviral immunity.

Animals↗

PubMed2004

Ionotropic glutamate receptor activated by N-methyl-D-aspartate: a key molecule of conscious life.

We want to propose that basic stereotyped integrative functions are the result of sequentially built neuronal circuits in the primitive regions of the brain in whose build-up a particular subunit composition iGluR-NMDA would play a central role. iGluR-NMDA is a multiregulated heteromeric glutamate receptor-ion channel found in plasma membranes of neurons and other cells. iGluR-NMDA may be composed of up to five subunits, depending on the type of cell involved and its location. There are three major types of subunits and there are variations within each type allowing for up to 13 possible subunits, at least in the rat, which differ from each other in amino acid sequence and thus, in tertiary structure. The actual iGluR-NMDA heteropolymer involved in a given function may thus have a great number of subunit composition possibilities which would be the result of the particular genes expressed in a given type of cell. The iGluR-NMDA is an ion channel that opens in response to glutamate in a highly regulated fashion in which different molecules and ions present in the interstitial fluid determine whether or not the channel opens upon glutamate binding. The original function of iGluR-NMDA may have been that of allowing calcium influx to cells. As the brain receives external stimuli through the senses, new circuits will be formed stepwise in the neocortex in which a particular subunit composition iGluR-NMDA will be involved. Differentiation between external stimuli generated circuits and those governing internal functions will allow distinction between self and non-self, thus generating conscious awareness. The role of the particular subunit composition iGluR-NMDA proposed would be that of providing a means of calcium influx to the synapses to be formed and, if the same stimulus is forthcoming, allowing permanent synapses formation through the membrane incorporation of calcium dependent adhesion molecules such as cadherins and cytoskeleton reorganization promoted by nectins.

Brain↗

PubMed2006

Different receptors binding to distinct interfaces on herpes simplex virus gD can trigger events leading to cell fusion and viral entry.

One of the herpes simplex virus envelope glycoproteins, designated gD, is the principal determinant of cell recognition for viral entry. Other viral glycoproteins, gB, gH and gL, cooperate with gD to mediate the membrane fusion that is required for viral entry and cell fusion. Membrane fusion is triggered by the binding of gD to one of its receptors. These receptors belong to three different classes of cell surface molecules. This review summarizes recent findings on the structure and function of gD. The results presented indicate that gD may assume more than one conformation, one in the absence of receptor, another when gD is bound to the herpesvirus entry mediator, a member of the TNF receptor family, and a third when gD is bound to nectin-1, a cell adhesion molecule in the immunoglobulin superfamily. Finally, information and ideas are presented about a membrane-proximal region of gD that is required for membrane fusion, but not for receptor binding, and that may have a role in activating the fusogenic activity of gB, gH and gL.

Cell Fusion↗

PubMed2005

Bioinformatic characterization of the SynCAM family of immunoglobulin-like domain-containing adhesion molecules.

SynCAM 1 (synaptic cell adhesion molecule 1, alternatively named Tslc1 and nectin-like protein 3) belongs to the immunoglobulin superfamily and is an adhesion molecule that operates in a variety of important contexts. Exemplary are its roles in adhesion at synapses in the central nervous system and as tumor suppressor. Here, I describe a family of genes homologous to SynCAM 1 comprising four genes found solely in vertebrates. All SynCAM genes encode proteins with three immunoglobulin-like domains of the V-set, C1-set, and I-set subclasses. Comparison of genomic with cDNA sequences provides their exon-intron structure. Alternative splicing generates isoforms of SynCAM proteins, and diverse SynCAM 1 and 2 isoforms are created in an extracellular region rich in predicted O-glycosylation sites. Protein interaction motifs in the cytosolic sequence are highly conserved among all four SynCAM proteins, indicating their critical functional role. These findings aim to facilitate the understanding of SynCAM genes and provide the framework to examine the physiological functions of this family of vertebrate-specific adhesion molecules.

Alternative Splicing↗

PubMed2001

Biochemical markers (without markers of infection) of the risk of preterm delivery. Implications for clinical practice.

BACKGROUND: New biochemical markers for the risk of spontaneous preterm birth (SPB) give a more precise and earlier diagnosis than the usual ones. We reviewed the data about the principal markers. RESULTS: Using studies with good methodology and a large number of subjects, we observe that the predictive value of these new markers is somewhat higher than those of the usual markers. Fetal fibro-nectin (FNf) and cervical ultrasound undeniably improve the identification of patients at risk of preterm birth, both in the general population and in these threatened preterm delivery. However no management has yet been demonstrated efficacious, especially in a general population so any recommendations for their systematic utilisation is premature. Other biochemical markers (salivary estriol, serum CRH, etc.) are still under assessment and should not be used outside research protocols. IMPLICATION FOR PRACTICE: It is appropriate to integrate either FNf or cervical ultrasound into daily clinical practice for patients with signs of preterm labor. These new indicators are of special use when the diagnosis is uncertain with the standard markers (uterine contractions, digital examination). Among these patients, they should reduce the number of hospitalizations and of useless treatments, because of their good negative predictive value. At the same time, for patients poorly 'labeled' by the clinical examination, they should allow the application of intensive management (intravenous tocolysis, corticoids, in utero transfers). CONCLUSION: Future studies should evaluate these tests in everyday practice. The objective is not to predict preterm birth but to prevent either it or its negative consequences. This goal will be met when we have an effective treatment, without associated adverse effects, to offer patients after a positive test result.

Biomarkers↗

PubMed2005

HSV vector-mediated transduction and GDNF secretion from adipose cells.

The accessibility of adipose tissue and its ability to secrete various bioactive molecules suggest that adipose cells may be attractive targets for gene therapy applications. Here, we report the use of highly defective herpes simplex virus (HSV) vectors as suitable gene transfer agents for adipose cells in culture and fat tissue in animals. Using an in vitro model of human adipose differentiation, we first demonstrated that mature adipocytes and their precursor cells express the two principal HSV viral entry receptors HveA and HveC (nectin-1) and are efficiently transduced at a low multiplicity of infection by HSV-lacZ reporter gene and glial cell line-derived neurotrophic factor (GDNF) gene vectors. Extended expression of beta-galactosidase and secretion of GDNF occurred in transduced fat tissue explants from rabbits. In vivo gene transfer to rabbit subcutaneous adipose tissue resulted in local GDNF expression for at least 2 months. These experiments establish the efficient transduction of adipose cells by HSV vectors and suggest that fat tissue may represent a useful site for HSV-mediated gene delivery with potential for therapeutic applications.

Adipocytes↗

PubMed2005

The pro-fusion domain of herpes simplex virus glycoprotein D (gD) interacts with the gD N terminus and is displaced by soluble forms of viral receptors.

Entry of herpes simplex virus into the cell requires the interaction of gD with one of its receptors, herpesvirus entry mediator or nectin 1, and the intervention of gB, gH, or gL, required to execute fusion of the virion envelope with cell membranes. The gD ectodomain is organized in two structurally and functionally differentiated regions. The N terminus (residues 1-260) carries the receptor binding sites, and the C terminus (residues 260-310) functions as the pro-fusion domain (PFD), which is required for viral infectivity and fusion but not for receptor binding. The objective of our studies is to elucidate how gD links receptor recognition to the triggering of fusion. Here, we show that PFD is made of subdomains 1 and 2 (amino acids 260-285 and 285-310). Each one partially contributed to herpes simplex virus infectivity. By means of glutathione S-transferase (GST) fusion proteins, we show that PFD bound soluble forms of gD, truncated at residue 260 (gD260t) or downstream. Both PFD subdomains bound gD260t, highlighting multiple contact sites between the N and C termini of gD. When gD260t was in complex with either receptor, it failed to bind GST-PFD. In turn, the receptors did not bind GST-PFD, irrespective of whether they were in complex with gD. Thus, gD260t interacted with the C terminus only if unbound to the receptor. We propose that (i) before receptor binding, gD adopts a "closed" conformation in which the N and C termini interact; and (ii) on encounter with a receptor, gD modifies its conformation and the N and C termini are released from reciprocal interactions ("opened" conformation) and enabled to trigger fusion.

Amino Acid Sequence↗

PubMed2006

Oligozoospermia with normal fertility in male mice lacking the androgen receptor in testis peritubular myoid cells.

Androgens and the androgen receptor (AR) play important roles in the testes. Previously we have shown that male total AR knockout (T-AR-/y) mice revealed incomplete germ cell development and lowered serum testosterone levels, which resulted in azoospermia and infertility. However, the consequences of AR loss in particular types of testicular cells remain unclear. Using a Cre-loxP conditional knockout strategy, we generated a tissue-selective knockout mouse with the AR gene deleted in testis peritubular myoid cells (PM-AR-/y). Phenotype analyses showed that PM-AR-/y mice were indistinguishable from WT AR (AR+/y) mice with the exception of smaller testes size. PM-AR-/y mice have serum testosterone concentrations comparable with AR+/y mice. PM-AR-/y mice have oligozoospermia in the epididymis; however, fertility was normal. Although normal germ cell distribution ratio was found, total germ cell number decreased in PM-AR-/y mice. Further mechanistic studies demonstrated that PM-AR-/y mice have defects in the expression of Sertoli cells' functional marker genes such as tranferrin, epidermal fatty acid-binding protein, androgen-binding protein, and other junction genes including occludin, testin, nectin, zyxin, vinculin, laminingamma3, gelsolin, connection43, and N-cadherin. Furthermore, there were defects in peritubular myoid cell contractility-related genes such as endothelin-1, endothelin receptor A and B, adrenomedullin, adrenomedullin receptor, and vasopressin receptor 1a. Together, our PM-AR-/y mice provide in vivo evidence for the requirement of functional AR in peritubular myoid cells to maintain normal Sertoli cells function and peritubular myoid cell contractility, thus ensuring normal spermatogenesis and sperm output.

Animals↗

PubMed2001

Interaction of the poliovirus receptor CD155 with the dynein light chain Tctex-1 and its implication for poliovirus pathogenesis.

The cellular receptor for poliovirus CD155 (or PVR) is the founding member of a new class of membrane-associated immunoglobulin-like proteins, which include the mouse tumor-associated antigen E4 (Tage4) and three proteins termed "nectins." Using a yeast two-hybrid screen we have discovered that the cytoplasmic domain of CD155 associates strongly and specifically with Tctex-1, a light chain of the dynein motor complex, the latter representing the major driving force for retrograde transport of endocytic vesicles and membranous organelles. We confirmed the interaction biochemically and by co-immunoprecipitation, and we mapped the Tctex-1 binding site to a SKCSR motif within the juxtamembrane region of CD155. Tctex-1 immunoreactivity was detected in mouse sciatic nerve and spinal cord (two tissues of central importance for poliovirus pathogenesis) in punctate, possibly vesicular, patterns. We propose that the cytoplasmic domain may target CD155-containing endocytic vesicles to the microtubular network. Neurotropic viruses like poliovirus, herpesvirus, rabies virus, and pseudorabies virus all utilize neuronal retrograde transport to invade the central nervous system. Association with Tctex-1 and, hence, with the dynein motor complex may offer an explanation for how poliovirus hijacks the cellular transport machinery to retrogradely ascend along the axon to the neuronal cell body.

Amino Acid Motifs↗

PubMed2002

Biochemical and structural definition of the l-afadin- and actin-binding sites of alpha-catenin.

alpha-Catenin is an integral component of adherens junctions, where it links cadherins to the actin cytoskeleton. alpha-Catenin is also required for the colocalization of the nectin/afadin/ponsin adhesion system to adherens junctions, and it specifically associates with the nectin-binding protein afadin. A proteolytic fragment of alpha-catenin, residues 385-651, contains the afadin-binding site. The three-dimensional structure of this fragment comprises two side-by-side four-helix bundles, both of which are required for afadin binding. The alpha-catenin fragment 385-651 binds afadin more strongly than the full-length protein, suggesting that the full-length protein harbors a cryptic binding site for afadin. Comparison of the alpha-catenin 385-651 structure with the recently solved structure of the alpha-catenin M-fragment (Yang, J., Dokurno, P., Tonks, N. K., and Barford, D. (2001) EMBO J. 20, 3645-3656) reveals a surprising flexibility in the orientation of the two four-helix bundles. alpha-Catenin and the actin-binding protein vinculin share sequence and most likely structural similarity within their actin-binding domains. Despite this homology, actin binding requires additional sequences adjacent to this region.

Actins↗

PubMed2006

Mast cell costimulation by CD226/CD112 (DNAM-1/Nectin-2): a novel interface in the allergic process.

Mast cells have critical effector functions in various immune reactions. In allergic inflammation, mast cells interact with tissue-infiltrating eosinophils, forming a regulatory unit in the late and chronic phases of the allergic process. However, the pathways and molecules within this unit are still largely undefined. Here, we show that human mast cells and eosinophils express DNAX accessory molecule 1 (DNAM-1, CD226) and its ligand Nectin-2 (CD112). CD226 synergizes with FcepsilonRI on mast cells, and its engagement augments degranulation through a pathway involving Fyn, linker of activation of T-cells, phospholipase C gamma2, and CD18. This pathway is subject to negative interference by inhibitory receptors and is completely inhibited by linking IgE with IRp60 (CD300a) using a bispecific antibody. Moreover, blocking CD112 expressed on eosinophils using neutralizing antibodies normalized the hyperactivity resulting from IgE-dependent activation of mast cells co-cultured with eosinophils. Our findings demonstrate a novel interface between these two effector cells, implicating relevance for in vivo allergic states. Moreover, costimulatory responses might be a critical component in allergic reactions and may therefore become novel targets for anti-allergic therapy.

Antigens, Differentiation, T-Lymphocyte↗

PubMed2004

Endocytosis of E-cadherin regulated by Rac and Cdc42 small G proteins through IQGAP1 and actin filaments.

E-cadherin is a key cell-cell adhesion molecule at adherens junctions (AJs) and undergoes endocytosis when AJs are disrupted by the action of extracellular signals. To elucidate the mechanism of this endocytosis, we developed here a new cell-free assay system for this reaction using the AJ-enriched fraction from rat liver. We found here that non-trans-interacting, but not trans-interacting, E-cadherin underwent endocytosis in a clathrin-dependent manner. The endocytosis of trans-interacting E-cadherin was inhibited by Rac and Cdc42 small G proteins, which were activated by trans-interacting E-cadherin or trans-interacting nectins, which are known to induce the formation of AJs in cooperation with E-cadherin. This inhibition was mediated by reorganization of the actin cytoskeleton by Rac and Cdc42 through IQGAP1, an actin filament-binding protein and a downstream target of Rac and Cdc42. These results indicate the important role of the Rac/Cdc42-IQGAP1 system in the dynamic organization and maintenance of the E-cadherin-based AJs.

Actin Cytoskeleton↗

PubMed2006

A novel role for phagocytosis-like uptake in herpes simplex virus entry.

It is becoming increasingly clear that herpesviruses can exploit the endocytic pathway to infect cells, yet several important features of this process remain poorly defined. Using herpes simplex virus-1 (HSV-1) as a model, we demonstrate that endocytosis of the virions mimic many features of phagocytosis. During entry, HSV-1 virions associated with plasma membrane protrusions followed by a phagocytosis-like uptake involving rearrangement of actin cytoskeleton and trafficking of the virions in large phagosome-like vesicles. RhoA GTPase was activated during this process and the mode of entry was cell type-specific. Clathrin-coated vesicles had no detectable role in virion trafficking as Eps15 dominant-negative mutants failed to affect HSV-1 uptake. Binding and fusion of the virion envelope with the phagosomal membrane is likely facilitated by clustering of nectin-1 (or HVEM) in phagosomes, which was observed in infected cells. Collectively, our data suggests a novel mode of uptake by which the virus can infect both professional and nonprofessional phagocytes.

Actins↗

PubMed2004

Fractionation of the epithelial apical junctional complex: reassessment of protein distributions in different substructures.

The epithelial apical junctional complex (AJC) is an important regulator of cell structure and function. The AJC is compartmentalized into substructures comprising the tight and adherens junctions, and other membrane complexes containing the membrane proteins nectin, junctional adhesion molecule, and crumbs. In addition, many peripheral membrane proteins localize to the AJC. Studies of isolated proteins indicate a complex map of potential binding partners in which there is extensive overlap in the interactions between proteins in different AJC substructures. As an alternative to a direct search for specific protein-protein interactions, we sought to separate membrane substructures of the AJC in iodixanol density gradients and define their protein constituents. Results show that the AJC can be fractured into membrane substructures that contain specific membrane and peripheral membrane proteins. The composition of each substructure reveals a more limited overlap in common proteins than predicted from the inventory of potential interactions; some of the overlapping proteins may be involved in stepwise recruitment and assembly of AJC substructures.

Animals↗

PubMed2006

Lmo7 is an emerin-binding protein that regulates the transcription of emerin and many other muscle-relevant genes.

X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) is inherited through mutations in emerin, a nuclear membrane protein. Emerin has proposed roles in nuclear architecture and gene regulation, but direct molecular links to disease were unknown. We report that Lim-domain only 7 (Lmo7) binds emerin directly with 125 nM affinity; the C-terminal half of human Lmo7 (hLmo7C) was sufficient to bind emerin in vitro. Lmo7 appeared relevant to EDMD because a deletion that removes Lmo7 (plus eight exons of a neighboring gene) in mice causes dystrophic muscles [Semenova, E., Wang, X., Jablonski, M.M., Levorse, J. and Tilghman, S.M. (2003) An engineered 800 kilobase deletion of Uchl3 and Lmo7 on mouse chromosome 14 causes defects in viability, postnatal growth and degeneration of muscle and retina. Hum. Mol. Genet., 12, 1301-1312]. Lmo7 localizes in the nucleus, cytoplasm and cell surface, particularly adhesion junctions [Ooshio, T., Irie, K., Morimoto, K., Fukuhara, A., Imai, T. and Takai, Y. (2004) Involvement of LMO7 in the association of two cell-cell adhesion molecules, nectin and E-cadherin, through afadin and alpha-actinin in epithelial cells. J. Biol. Chem., 279, 31365-31373]. Our data suggest endogenous Lmo7 is a nucleocytoplasmic shuttling protein, and might also localize at focal adhesions in HeLa cells. Two key results show that Lmo7 regulates emerin gene expression: rat Lmo7 isoforms directly activated a luciferase reporter gene in vivo, and emerin mRNA expression decreased 93% in Lmo7-downregulated HeLa cells. Thus, Lmo7 not only binds emerin protein but is also required for emerin gene transcription. Microarray analysis of Lmo7-downregulated HeLa cells identified over 4200 misregulated genes, including 46 genes important for muscle or heart. Misregulation of 11 genes, including four (CREBBP, NAP1L1, LAP2, RBL2) known to be misregulated in X-EDMD patients and emerin-null mice [Bakay, M., Wang, Z., Melcon, G., Schiltz, L., Xuan, J., Zhao, P., Sartorelli, V., Seo, J., Pegoraro, E., Angelini, C. et al. (2006) Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration. Brain, 129, 996-1013; Melcon, G., Kozlov, S., Cutler, D.A., Sullivan, T., Hernandez, L., Zhao, P., Mitchell, S., Nader, G., Bakay, M., Rottman, J.N. et al. (2006) Loss of emerin at the nuclear envelope disrupts the Rb1/E2F and MyoD pathways during muscle regeneration. Hum. Mol. Genet., 15, 637-651] was confirmed by real-time PCR. Overexpression of wild-type emerin, but not emerin mutant P183H (which causes EDMD and selectively disrupts binding to Lmo7), decreased the expression of CREBBP, NAP1L1 and LAP2, suggesting Lmo7 activity is both EDMD-relevant and inhibited by direct binding to emerin. We conclude that Lmo7 positively regulates many EDMD-relevant genes (including emerin), and is feedback-regulated by binding to emerin.

Cell Membrane↗

PubMed2005

Heterotypic interaction of CRTAM with Necl2 induces cell adhesion on activated NK cells and CD8+ T cells.

NK cells and CD8+ T cells exhibit cytotoxicity and cytokine production upon recognizing target cells through cell-cell interaction. We screened the molecules involved in the recognition and regulation of these cells using cDNA subtraction between naive and activated NK cells. We identified class I-restricted T cell-associated molecule (CRTAM), a two Ig domain-bearing surface receptor, as a molecule rapidly and transiently expressed on NK cells and CD8+ T cells upon activation. CRTAM is expressed as a dimer on the cell surface, and its expression is transcriptionally regulated. Using an expression-cloning system, we then further identified Nectin-like (Necl) molecule 2, a three Ig domain-containing receptor, as a ligand of CRTAM. While Necl2 mediates homotypic interaction, CRTAM interacts with Necl2 but not with CRTAM itself. The heterotypic CRTAM-Necl2 interaction has a higher affinity than the homotypic Necl2 interaction. Although there was no clear alteration in the cytotoxic function of the NK cells and CD8+ T cells against the Necl2-expressing target cells, T cells expressing CRTAM tightly bound to Necl2-expressing cells. CRTAM+ cells did not induce homotypic aggregation but they did exert strong heterotypic binding with Necl2+ cells, which was inhibited by the addition of the CRTAM-Ig fusion protein. These results suggest that the heterotypic interaction between CRTAM and Necl2 plays an important role in the adhesion, interaction or migration of NK cells and CD8+ T cells upon stimulation.

Animals↗