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Results for “Hepatitis A Virus Cellular Receptor 2”

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At least 19 recordsLinked to original sources

PubMed2006

Human membrane protein Tim-3 facilitates hepatitis A virus entry into target cells.

In this study, a cellular surface membrane protein of immunoglobulin (Ig) superfamily (IgSF) was identified from a human dendritic cell (DC) cDNA library by large-scale random sequencing, which is identical to previously reported Tim-3 (T-cell Ig- and mucin-domain-containing molecule 3). Recent data have suggested the association of the 281-residue mouse Tim-3 molecule with Th1-related T cell responses and disease in mice. Human Tim-3 is a 301-residue type I membrane protein whose extracellular region contains a Cys-rich Ig-like domain and a mucin domain, the characteristics of Tim proteins. It shows significant homology to human hepatitis A virus (HAV) cellular receptor-1 (HuHAVcr-1)/Tim-1. Human Tim-3 mRNA was highly expressed in monocytes or monocyte-derived cells, and the expression level decreased when DC underwent maturation and activation. There is no previous report on the biological functions of human Tim-3, especially the involvement in virus infection. We demonstrated that HeLa cells, which are refractory to HAV infection, acquired a limited susceptibility to HAV infection after stably overexpressing human Tim-3 as confirmed by Western blot analysis using anti-Tim-3 antibody, but Tim-3-Fc fusion protein had no direct HAV-binding activity. The results indicated that human Tim-3 can promote HAV entry into target cells but itself may not function as a cellular receptor of HAV.

Amino Acid Sequence↗

PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗

PubMed2003

Genetic analysis of the influence of neuroantigen-complete Freund's adjuvant emulsion structures on the sexual dimorphism and susceptibility to experimental allergic encephalomyelitis.

The induction of organ-specific autoimmune diseases, such as experimental allergic encephalomyelitis (EAE) the principal animal model of multiple sclerosis (MS), relies on the use of complete Freund's adjuvant (CFA) emulsions. In this study we report that the physical structure of the particles comprising neuroantigen-CFA emulsions significantly influences the genetic control of the incidence and sexual dimorphism seen in EAE. Immunization of (B10.S/SgMcdJ x SJL/J) F(2) mice segregating the quantitative trait loci (QTL) controlling EAE in susceptible SJL/J and resistant B10.S/SgMcdJ mice with emulsions consisting of particles where the Mycobacterium tuberculosis and neuroantigens are localized on the phase surfaces led to severe EAE in 98.8% of the mice, overriding all sex-specific and non-sex-specific genetic checkpoints. In contrast, F(2) mice immunized with emulsions where the bacterial products and encephalitogens are buried inside the water/oil vesicles exhibited a significant reduction in disease incidence (7.5%) and a sexual dimorphism (5% male versus 10% female). A genome scan identified QTL on chromosomes 7 and 11 controlling the sexual dimorphism as a function of the physical structure of the emulsion. The chromosome 11 QTL co-localizes with eae6b, and with Il12b and heptatitis A virus cellular receptor 2 (Havcr2, formerly known as Timd3), both of which are candidate genes for this QTL. Sequence analysis of the SJL/J and B10.S/SgMcdJ alleles indicates that both gene products are structurally monomorphic. Expression analysis also excluded both as candidates for this sex-specific QTL. These results reinforce the importance of gene-environment interactions in initiating and propagating autoimmune disease of the central nervous system, particularly in the context of susceptibility to MS and disease heterogeneity.

Amino Acid Sequence↗

PubMed2003

The TIM gene family: emerging roles in immunity and disease.

The search for cell-surface markers that can distinguish T helper 1 (T(H)1) cells from T(H)2 cells has led to the identification of a new gene family, encoding the T-cell immunoglobulin mucin (TIM) proteins, some of which are differentially expressed by T(H)1 and T(H)2 cells. The role of the TIM-family proteins in immune regulation is just beginning to emerge. Here, we describe the various TIM-family members in mice and humans, and discuss the genetic and functional evidence for their role in regulating autoimmune and allergic diseases.

Animals↗

PubMed2005

Genetic variants of the T-cell immunoglobulin mucin 1 but not the T-cell immunoglobulin mucin 3 gene are associated with asthma in an African American population.

BACKGROUND: The T-cell immunoglobulin mucin ( TIM ) proteins and their genetic variants have been suggested to play a role in regulating allergic diseases. OBJECTIVE: Genetic association of the sequence variants for TIM-1 and TIM-3 genes with asthma in an African American population was investigated. METHODS: Both case-control and family-based association analyses were performed for a total of 7 polymorphisms, including 3 single nucleotide polymorphism (SNPs) and 1 insertion/deletion polymorphism in the TIM-1 and 3 SNPs in the TIM-3 genes. The exposure to hepatitis A virus as judged by seropositivity was also examined. RESULTS: In the case-control design, the frequencies of the TT genotype for SNP rs2277025 and the homozygous deletion variant (157delMTTTVP) in the fourth exon of the TIM-1 gene were higher among patients with patients with asthma compared with the controls (odds ratio [OR], 2.779, P = .016; and OR, 3.09, P = .022, respectively). This association was substantiated by haplotype analysis of these and 2 additional SNPs (OR, 2.48; P = .004), and also by family-based tests for the allele and haplotype carrying 157delMTTTVP (P = .009 and P = .048, respectively). Furthermore, this association seems to exist even in the hepatitis A virus-seronegative subjects in our data. None of the 3 variants in TIM-3 genes yielded significant association with either asthma or asthma-related phenotypes. CONCLUSION: Our findings suggest that the genetic variants of the TIM-1 but not the TIM-3 gene contribute to asthma susceptibility in this African-American population.

Adult↗

PubMed2005

Tim-3+ T-bet+ tumor-specific Th1 cells colocalize with and inhibit development and growth of murine neoplasms.

Although T cells infiltrate many types of murine and human neoplasms, in many instances tumor-specific cytotoxicity is not observed. Strategies to stimulate CTL-mediated antitumor immunity have included in vitro stimulation and/or genetic engineering of T cells, followed by adoptive transfer into tumor-bearing hosts. In this model of B cell lymphoma in SJL/J mice, we used Tim-3(+) T-bet(+) Th1 cells to facilitate the development of tumor-specific CTL. Tumor-specific Th1 cell lines were polarized with IL-12 during in vitro stimulation and long term maintenance. As few as 5 million Tim-3(+) T-bet(+) Th1 cells enabled recipients to resist growth of malignant transplantable cells. In addition, similar numbers of Th1 cells injected into 2- to 3-mo-old mice inhibited development of the spontaneous primary lymphomas, which normally arise in 90% of aging mice. CFSE(+) Th1 cells colocalized with injected tumor cells in vivo and formed conjugates with the tumor cells within follicles, whereas in nontumor-challenged recipients the CFSE(+) Th1 cells localized only within the T cell zones of the spleen. These results provide evidence that adoptive immunotherapy with Tim-3(+) T-bet(+) tumor-specific Th1 cells can be used to induce host cytotoxic responses that inhibit the development and growth of neoplastic cells.

Adoptive Transfer↗

PubMed2005

Tim-2 regulates T helper type 2 responses and autoimmunity.

Identification of the T cell immunoglobulin mucin-domain containing (Tim) gene family introduced a new family of cell surface molecules that is involved in the regulation of immune responses. We previously demonstrated that Tim-3 is expressed on terminally differentiated T helper (Th)1 cells, and serves to regulate Th1 immune responses. Here, we describe the identification and function of Tim-2, a novel member of the Tim gene family. In contrast with Tim-3, we demonstrate that Tim-2 is expressed preferentially in differentiated Th2 cells. Blockade of the Tim-2/Tim-2 ligand interaction, by administration of soluble Tim-2 fusion protein (Tim-2 immunoglobulin [Ig]), results in T cell hyperproliferation and the production of Th2 cytokines. Administration of Tim-2 Ig during the induction phase reduces the severity of experimental autoimmune encephalomyelitis, a Th1-mediated autoimmune disease model of multiple sclerosis. We propose that Tim-2, an orthologue of human Tim-1, is critical for the regulation of Th2 responses during autoimmune inflammation.

Animals↗

PubMed2006

Establishment of stable high expression cell line with green fluorescent protein and resistance genes.

In order to establish stable high expression cell lines, the eukaryotic expression vector pIRES2EGFP and recombinant plasmid pIRES2EGFP-TIM-3 were transfected into mammalian cells CHO by Lipofectamine. The transfected cells were cultivated under selective growth medium including G418 and green fluorescent protein (GFP) positive cells were sorted by FACS. Simultaneously, growing transfectants were selected only by G418 in the medium. The GFP expression in stably transfected cells was detected by FACS. Under selective growth conditions with G418, the percentage of GFP positive cells was reduced rapidly and GFP induction was low. In contrast, the percentages of GFP positive cells were increased gradually after FACS. By 3 rounds of GFP selection, the stable high expression cell lines were established. Furthermore, using FACS analysis GFP and the target protein TIM-3 co-expression in the stable transfectants cultured in nonselective medium was detected. Theses results demonstrated that the stably transfected cell lines that express high titer of recombinant protein can be simply and fleetly obtained by using GFP and selective growth medium.

Animals↗

PubMed2004

The role of ICOS and other costimulatory molecules in allergy and asthma.

Activation and differentiation of T cells play a critical role in the pathogenesis of allergies and asthma. Upon encounter with specific antigen, naïve T helper precursor (ThP) cells become activated, an event that is regulated not only by engagement of the T cell receptor (TCR) with peptide presented in the context of MHC class II molecules, but also by a number of costimulatory signals. CD28 engagement by B7-1 and B7-2 on resting ThP cells provides a critical signal for initial cell cycle progression, interleukin-2 production and clonal expansion. However, in recent years, other related members of the immunoglobulin (Ig) family, such as inducible costimulatory molecules (ICOS) and the TNF receptor family members which include OX40, have also been demonstrated to play an important role in providing unique and complementary signals that regulate the outcome of immune responses. These positive costimulatory signals are counterbalanced by signals that dampen down immune responses and include CTLA-4, PD-1 and the recently described Ig superfamily members BTLA and TIM-3. This review discusses the role of these costimulatory signals and their potential involvement in the pathogenesis of asthma and allergic responses.

Animals↗

PubMed2006

A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by its ligand galectin-9.

Tim-3 is a member of the TIM family of proteins (T-cell immunoglobulin mucin) involved in the regulation of CD4+ T-cells. Tim-3 is a T(H)1-specific type 1 membrane protein and regulates T(H)1 proliferation and the development of tolerance. Binding of galectin-9 to the extracellular domain of Tim-3 results in apoptosis of T(H)1 cells, but the intracellular pathways involved in the regulatory function of Tim-3 are unknown. Unlike Tim-1, which is expressed in renal epithelia and cancer, Tim-3 has not been described in cells other than neuronal or T-cells. Using RT-PCR we demonstrate that Tim-3 is expressed in malignant and non-malignant epithelial tissues. We have cloned Tim-3 from an immortalized liver cell carcinoma line and identified a highly conserved tyrosine in the intracellular tail of Tim-3 (Y265). We demonstrate that Y265 is specifically phosphorylated in vivo by the interleukin inducible T cell kinase (ITK), a kinase which is located in close proximity of the TIM genes on the allergy susceptibility locus 5q33.3. Stimulation of Tim-3 by its ligand galectin-9 results in increased phosphorylation of Y265, suggesting that this tyrosine residue plays an important role in downstream signalling events regulating T-cell fate. Given the role of TIM proteins in autoimmunity and cancer, the conserved SH2 binding domain surrounding Y265 could represent a possible target site for pharmacological intervention.

Amino Acid Sequence↗

PubMed2006

Antibodies to T-cell Ig and mucin domain-containing proteins (Tim)-1 and -3 suppress the induction and progression of murine allergic conjunctivitis.

The T cell Ig and mucin domain-containing proteins (Tim) regulate Th1- and Th2-mediated immune responses. We investigated the ability of Abs blocking Tim-1 or Tim-3 ligand-binding activity to prevent and treat murine experimental allergic conjunctivitis (EC), a Th2-mediated disease. Treatment with either Ab during the induction phase of EC in actively immunized wild-type mice suppressed EC and upregulated Th1 and Th2 immune responses. In contrast, both Abs exacerbated EC in actively immunized IFN-gamma-knockout mice. Thus, both anti-Tim Abs suppress the pathogenic immune responses generated in the induction phase by upregulating systemic IFN-gamma production. Treatment of actively immunized mice and passively immunized mice with either anti-Tim Ab just prior to RW challenge also suppressed EC. Thus, treatment with anti-Tim-1 or anti-Tim-3 Ab can suppress both the induction and progression of EC, which could indicate potential preventive and/or therapeutic approaches for allergic diseases such as allergic conjunctivitis.

Animals↗

PubMed2006

TIM-3 in autoimmunity.

T cell immunoglobulin and mucin domain (TIM)-3 is a molecule expressed on terminally differentiated murine Th1 cells but not on Th2 cells. Identification of galectin-9 as a ligand for TIM-3 has now firmly established the TIM-3-galectin-9 pathway as an important regulator of Th1 immunity and tolerance induction. TIM-3 is similarly expressed on human Th1 cells and not on Th2 cells, which suggests that TIM-3 might also contribute to Th1 regulation in humans. In addition, genetic data associate the TIM locus and specific TIM-3 polymorphisms with various immune-mediated diseases. Most importantly, recent data suggest a novel paradigm in which dysregulation of the TIM-3-galectin-9 pathway could underlie chronic autoimmune disease states, such as multiple sclerosis.

Animals↗

PubMed2004

The association of TIM-3 gene polymorphism with atopic disease in Korean population.

The family of T-cell immunoglobulin domain and mucin domain (TIM) proteins is identified to be expressed on T cells. A member of the TIM family, TIM-3 is selectively expressed on the surface of differentiated T helper 1 (Th1) cells. TIM-3 might have an important role in the induction of autoimmune diseases by regulating macrophage activation and interacts with the TIM-3 ligand to regulate Th1 responses. In the present study, we analyzed the association of the genotype and allele frequencies between asthma or allergic rhinitis patients and nonatopic controls using large samples size at -1516G > T, -574T > G, and 4259G > T polymorphic sites of the Tim-3 gene. The genotype and allele frequencies of -574T > G polymorphism in asthma patients (p = 0.042 and p = 0.017, respectively) as well as allergic rhinitis patients (p = 0.008 and p = 0.003, respectively) were significantly different from those of nonatopic controls. Furthermore, the allele frequency of 4259G > T polymorphism in allergic rhinitis patients (p = 0.029) was also significantly different. Our results strongly suggest that the -574T > G polymorphism of Tim-3 might be associated with the susceptibility of atopic diseases such as asthma and allergic rhinitis.

Adult↗

PubMed2004

The polymorphisms of Th1 cell surface gene Tim-3 are associated in a Korean population with rheumatoid arthritis.

The family of T-cell immunoglobulin domain and mucin domain (TIM) proteins is identified to be expressed on T cells. A member of TIM family, TIM-3 is selectively expressed on the surface of differentiated Th1 cells. TIM-3 might have an important role in the induction of autoimmune diseases by regulating macrophage activation and interacts with TIM-3 ligand to regulate Th1 responses. In the present study, we analyzed the association of the genotype and allele frequencies between rheumatoid arthritis (RA) patients and the controls without RA using large samples size at the -1516G>T, -574T>G and 4259G>T polymorphic sites of human Tim-3 gene. We further investigated the relationships between the genotypes of each single nucleotide polymorphisms (SNPs) and C-reactive protein (CRP) or rheumatoid factor (RF) levels in RA patients. The genotype and allele frequencies of the -574T>G (P = 0.001 and 0.001, respectively) as well as the 4259G>T (P = 0.001 ands 0.003, respectively) between RA patients and non-RA controls were significantly different. These results strongly suggest that -574T>G and 4259G>T polymorphism of the Tim-3 might be associated with susceptibility to RA.

Adult↗

PubMed2004

Protective DNA vaccination against experimental autoimmune encephalomyelitis is associated with induction of IFNbeta.

DNA vaccines encoding encephalitogenic peptides protect against subsequent development of rat experimental autoimmune encephalomyelitis (EAE) through unknown mechanisms. We investigated immune cell phenotypes at different time points after DNA vaccination with vaccine encoding myelin oligodendrocyte glycoprotein peptide 91-108 and subsequent induction of EAE. In protected rats, we observed (i) no alterations in antigen-specific Th2 or Th3 responses, (ii) reduced MHC II expression on splenocytes early after EAE induction, (iii) antigen-specific upregulation of IFNbeta upon recall stimulation and (iv) reduced IL-12Rbeta2 on lymphocytes. We suggest that the underlying mechanism of DNA vaccination is associated with immunomodulation exerted by induced IFNbeta.

Animals↗

PubMed2005

Expression of T cell immunoglobulin- and mucin-domain-containing molecules-1 and -3 (TIM-1 and -3) in the rat nervous and immune systems.

Expression of T cell immunoglobulin- and mucin-domain-containing molecules (TIMs) can be used as T helper (Th) differentiation markers in the human and mouse. We examined the expression of TIM-1 and -3 mRNAs in rat MBP(63-88)-induced experimental autoimmune encephalomyelitis (EAE). TIM-3 expression was upregulated in the spinal cord during EAE and following antigen restimulation of the encephalitogenic TCRBV8S2+ population. Interestingly, TIM-3 expression was also detected by in situ hybridization in resident cells of the nervous system. TIM-1 was expressed in B cells but not in resident CNS cells and TIM-1 mRNA levels in spinal cord were unchanged throughout the course of EAE. These results support the notion that TIM-3 can also be used as a Th1 differentiation marker in the rat. However, expression of TIM-1 and -3 is not restricted solely to T cells and the presence of TIM-3 in resident CNS cells may indicate a role for this molecule in the interaction between the nervous and immune systems.

Animals↗

PubMed2005

The TIM gene family regulates autoimmune and allergic diseases.

The recently identified TIM gene family encodes cell-surface receptors that are involved in the regulation of Th1- and Th2-cell-mediated immunity. Tim-3 protein is specifically expressed on Th1 cells and negatively regulates Th1 responses, whereas Tim-2 is preferentially expressed in Th2 cells. Tim-1, previously identified as the hepatitis A virus receptor, co-stimulates T-cell expansion and cytokine production. Tim-4, which is preferentially expressed on mature dendritic cells, is the ligand for Tim-1. In mouse models of asthma and multiple sclerosis, affecting the function of Tim molecules altered disease phenotype. Because TIM molecules are differentially expressed on effector Th1 and Th2 cells, further understanding of the mechanisms by which they regulate Th1- and Th2-effector functions will probably provide opportunities for the therapeutic modulation of immune-mediated diseases.

Animals↗

PubMed2006

Mouse model of respiratory Chlamydia pneumoniae infection for a genomic screen of subunit vaccine candidates.

An inbred A/J mouse respiratory challenge model was validated for vaccine testing against Chlamydia (C.) pneumoniae and used to screen the C. pneumoniae genome for vaccine candidates by expression library immunization (ELI). Biolistic delivery of genetic vaccine constructs elicited Th2-like immunity that was associated with inefficient elimination of C. pneumoniae. Delivery by injection elicited protective Th1-like responses. Since biolistic delivery of pools of ORFs was used in first round screening, the screen presumably selected against potent immunogens. Nevertheless, it was sufficiently accurate to identify three weakly protective antigens among all putative C. pneumoniae ORFs. The results suggest ELI discovery of highly protective C. pneumoniae vaccine candidates requires tight control of the Th1 immunity elicited by the genetically delivered library of test antigens.

Animals↗