Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study compares the mitogen-activated protein (MAP) kinase responses in T cells activated with the CD28 ligands B7-1 (CD80) and B7-2/B70 (CD86). Ligands B7-1 and B7-2 do not activate the Raf-1/ERK2 cascade, but share the ability to activate related Jun kinases. These natural ligands for CD28 had no stimulatory effect alone on Jun kinase activation, but the data show that B7-1 and B7-2 could both co-operate with intracellular Ca2+ increase and protein kinase C (PKC) activation to stimulate Jun kinases. The present study shows that the interaction of CD28 with its ligands B7-1 and B7-2 can induce identical signal transduction through the MAP kinase cascades.
Mol Immunol 1996 Jan
PMID:CD28 signal transduction pathways. A comparison of B7-1 and B7-2 regulation of the map kinases: ERK2 and Jun kinases. 860 25

The binding of CD40 ligand on activated T cells to CD40 on resting B cells induces the expression of costimulatory molecules B7-1 (CD80) and B7-2 (CD86). The induction of B7 molecules by CD40 ligand-CD40 interaction represents a critical step in rendering B cells competent for antigen presentation. The CBA/N mouse has a defect in CD40 signalling which has been attributed to a mutation in Bruton's tyrosine kinase. We have compared the ability of murine CD40 ligand to induce B7-1 and B7-2 expression on B cells isolated from CBA/N and wild-type CBA/J mice. We find that the CBA/N defect partially impairs both B7-1 and B7-2 induction via CD40. Subsequent experiments investigated the roles of different second messenger systems in B7-1 and B7-2 induction in normal B cells. In M12 B lymphomas either CD40 cross-linking or cAMP treatment can induce B7 molecules. Here we report that treatment with dibutyryl-cAMP also induces B7 molecules in normal B cells provided that they have been preactivated by CD40 cross-linking. We also find that PMA and ionomycin treatment of B cells induces B7-2 but not B7-1 expression. Our data therefore show roles for BTK, cAMP and PMA/ionomycin in B7 induction, as well as providing further evidence for differential regulation of B7-1 and B7-2 induction in B cells.
Mol Immunol 1996 Apr
PMID:Induction of costimulatory molecules B7-1 and B7-2 in murine B cells. the CBA/N mouse reveals a role for Bruton's tyrosine kinase in CD40-mediated B7 induction. 870 Jan 70

Lung dendritic cells (DCs) from mice were enriched to 92-99% purity using a multistep enrichment protocol which included fluorescence-activated cell sorting. DCs were analyzed for expression of cell surface molecules, function in a mixed leukocyte reaction (MLR), and dependence on accessory molecules in stimulating an MLR. DCs possessed potent accessory properties in vitro, while interstitial macrophages (IM), which are Ia-negative, displayed little MLR-stimulating function of their own. However, IM were capable of enhancing DC-initiated T cell proliferation via a cell contact mechanism. These results indicated that murine lung DCs functioned as stimulators of primary T cell responses, and that cells in the local environment influenced their function. Lung DCs expressed surface molecules typical of DCs from other sites including CD11a, CD54, CD80, and CD86. As is true for DCs in other sites, costimulatory molecules including CD80, CD86, CD40L, CD2, CD54, and CD11a played important roles in lung DC-initiated T cell proliferation. Interestingly, anti-CD86 monoclonal antibody (mAb) had little inhibitory effect on the MLR unless it was added in combination with anti-CD80 mAb. These studies suggest that CD80 on lung DCs can provide a costimulatory signal to allogeneic T cells in the absence of CD86 signaling, but that CD86 functions poorly except when CD80 is also engaged.
Am J Respir Cell Mol Biol 1997 Mar
PMID:Characterization of accessory molecules in murine lung dendritic cell function: roles for CD80, CD86, CD54, and CD40L. 930 14

Alveolar macrophages (AM) from sarcoid patients have been shown to be good antigen presenting cells (APC) unlike normal AM which are usually ineffective. We demonstrate in ten consecutive sarcoid patients that most of their AM, unlike normal AM, do coexpress high levels of CD86, CD40, and CD30L, all known to be important for T-cell activation. CD80 is also slightly more expressed on sarcoid AM than on normal AM, but is detected on only 26 +/- 6% (mean +/- SEM) of sarcoid AM. A good correlation is present between the percentage of sarcoid AM expressing CD86 and CD40 or CD86 and CD30L. However, no correlation is found between the percentage of CD80 and CD86 positive AM in these same patients. Blocking antibodies against CD86 were able to reduce by more than 80% allogeneic T-cell proliferation induced by the AM of sarcoid patients. This study provides evidence that AM can, in pathologic states such as sarcoidosis, express functional costimulatory molecules for T-cell activation such as CD86, thought to be rather specific for more professional APC such as dendritic cells.
Am J Respir Cell Mol Biol 1997 Jul
PMID:Alveolar macrophages in sarcoidosis coexpress high levels of CD86 (B7.2), CD40, and CD30L. 922 14

A selectivity of B7.1 (CD80) for promoting Th1 responses and B7.2 (CD86) for promoting Th2 responses in the murine system has recently been suggested. The present study explores this hypothesis, using human PBMCs and antigen-specific Th1 and Th2 clones. Proliferative responses of peripheral blood mononuclear cells (PBMCs) from ragweed-allergic, tetanus toxoid-immunized individuals were downregulated by treatment with anti-CD86 in ragweed- and tetanus toxoid-driven cultures (% Inhibition = 55 +/- 4 and 61 +/- 12, respectively; P < 0.03 relative to untreated cultures). Gene expression in PBMCs for interleukin (IL)-4, IL-5, and interferon gamma (IFNgamma), assessed by reverse-transcriptase polymerase chain reaction, was also downregulated by treatment with anti-CD86 in both the ragweed- and tetanus toxoid-driven systems. Neither independent efficacy nor synergy with anti-CD86 was apparent with anti-CD80 treatment; two different anti-CD80 blocking antibodies yielded identical results. Conversely, antigen-specific Th1 and Th2 clones were insensitive to treatment with either anti-CD80, anti-CD86, or a combination of the two. Unaffected parameters included proliferative response (P < 0.14 and 0.33, respectively, for Th1 and Th2), proinflammatory cytokine gene expression, and cytokine protein secretion into culture supernatants (P < 0.44 and 0.16, respectively, for IL-4 and IFNgamma). We conclude that CD86 is the primary B7 signaling homologue in human PBMC responses, and that second signal pathways through the B7 homologues have no effect on phenotypically differentiated T helper cells in humans.
Am J Respir Cell Mol Biol 1997 Aug
PMID:Differential regulation of human, antigen-specific Th1 and Th2 responses by the B-7 homologues, CD80 and CD86. 927 12

CD28/CD152-CD80/CD86 receptor-ligand interactions result in costimulatory signals critical for optimal T cell activation. CD28/CD152 and CD80/CD86 are members of the immunoglobulin superfamily (IgSF). Despite common receptor-ligand interactions, both receptor and ligand pairs share only limited sequence identity. A detailed molecular model of the extracellular Ig-like domain of human CD28 was constructed using a combination of different modeling methods. The model was based on the solution structure of CD152 and sequence comparison of the CD28/CD152 family. Assessment of the model revealed good stereochemical quality and sequence-structure compatibility. The CD28 model was used to map surface residues, N-linked glycosylation sites, and to compare residue conservation in CD28 and CD152. The location of N-linked glycosylation sites in CD28/CD152 restricts the surface area available for binding. Rigorous sequence conservation in CD28 and CD152 is limited to core IgSF consensus positions and surface residues implicated in ligand binding. Other surface residues vary greatly in CD28/CD152. Residues critical for ligand binding are surrounded by surface patches conserved only in either CD28 or CD152.
J Mol Graph Model 1997 Apr
PMID:Molecular modeling of CD28 and three-dimensional analysis of residue conservation in the CD28/CD152 family. 938 61

Asthma is a complex disorder characterized by airway hyperreactivity and inflammation. To analyze cellular interactions required for the secretion of cytokines by the bronchial mucosa, we have evaluated the ex vivo response of tissue explants to allergen. Endobronchial mucosal biopsy tissue from mild atopic asthmatic subjects and normal control subjects were maintained in culture for 24 h. To detect reactivity to allergen, the explants were stimulated with dust mite extract Dermatophagoides pteronyssinus (Der p). Our analysis revealed that without any overt stimulation, mRNA transcripts for interleukin (IL)-5 and IL-13 were expressed by asthmatic but not normal bronchial tissue. In contrast, the expression of interferon-gamma was observed in a higher proportion of cultured bronchial biopsies from the normal control subjects than in those from asthmatic subjects. Addition of Der p allergen did not change the cytokine profile of the explants from control volunteers but augmented the expression of IL-5 mRNA and induced secretion of the protein by the asthmatic bronchial tissue. In most cases, allergen also increased the production of IL-13 by bronchial tissue from asthmatic subjects. The allergen-induced secretion of IL-5 and IL-13 was inhibited by the fusion protein CTLA-4Ig, reflecting a requirement for CD80 (B7-1) and/or CD86 (B7-2) costimulation for the expression of the Th2 cytokines. This requirement for B7/CD28 costimulation is consistent with the hypothesis that IL-5 and IL-13 are produced by allergen-specific T cells resident in the asthmatic bronchial mucosa.
Am J Respir Cell Mol Biol 1999 Jan
PMID:B7 costimulation is required for IL-5 and IL-13 secretion by bronchial biopsy tissue of atopic asthmatic subjects in response to allergen stimulation. 987 Sep 29

We investigated accessory cell function, antigen (Ag) trafficking, and uptake of immune complexes in isolated nasal epithelial cells (NEC) and airway epithelial cells (AEC), as well as in the two respiratory epithelial cell lines A549 and BEAS-2B. The NEC and AEC were capable of supporting Ag-specific as well as phytohemagglutinin-induced and anti-CD3 antibody-induced T-cell proliferation. We colocalized fluorescein isothiocyanate (FITC)-labeled Ags with human leukocyte antigen (HLA)-DR in A549 and BEAS-2B, utilizing laser confocal microscopy. Respiratory epithelial cells stimulated and unstimulated with interferon (IFN)-gamma were pulsed with FITC-labeled Ags for varying periods and evaluated for their ability to internalize Ag. In the unstimulated cells, intracellular punctate staining was evident at 60 min and persisted up to 120 min. In the IFN-gamma-stimulated cells (100 U/ml for 48 h), uptake occurred at 30 min, was maximal at 60 min, and diminished at 120 min. We conducted kinetic studies in the A549 and BEAS-2B cells, utilizing electron microscopy with colloidal gold-conjugated Ags (Au-OVA). At 15 min, Au-OVA was evident in the early compartments resembling the compartment of uncoupling of receptor and ligand. At 30 min, multivesicular bodies were labeled with Au-OVA, and by 60 min Au-OVA was present in the primary and secondary lysosomes. The FITC-labeled Ags colocalized with an early endosomal marker (anti-cathepsin D), a late endosomal marker (M6PR), a lysosomal marker (CD63), and with 3-(2, 4-dinitroanilino)-3'-aminomethyldipropylamine, a marker of acidic vesicles. The BEAS-2B and A549 cells, and NEC and AEC, expressed surface Fcgamma receptor and internalized IgG immune complexes. The NEC and AEC also expressed the costimulatory molecules CD80 and CD86 as determined with flow cytometry, the reverse transcription-polymerase chain reaction for RNA, and immunohistochemistry, and T-cell proliferation could be blocked by treating NEC and AEC with anti-CD80 and anti-CD86 antibodies. Our findings suggest that respiratory epithelial cells may have a role in local Ag presentation.
Am J Respir Cell Mol Biol 1999 Sep
PMID:Antigen trafficking and accessory cell function in respiratory epithelial cells. 1046 Jul 54

Previous studies have shown that the pan CD28/cytotoxic T lymphocyte antigen (CTL)A-4 antagonist CTLA4 immunoglobulin (Ig) inhibits eosinophilic airway inflammation in Schistosoma mansoni-sensitized and airway-challenged mice. In the present study, the importance of CD28 as well as the individual roles of CD80 and CD86 were examined in this system using wild-type and CD28 knockout (KO) mice. Unlike wild-type controls, CD28KO mice did not produce systemic IgE or eosinophilic airway inflammation after antigen challenge. However, a lymphocytic infiltrate and continued production of interferon-gamma was observed in these animals. Thus, CD28 is not essential for the initial recruitment of lymphocytes into antigen-challenged airways but critically regulates the allergic T-helper 2 phenotype. We next determined by polymerase chain reaction and flow cytometry that CD80 and CD86 molecules are constitutively expressed in the naive murine lung and on eosinophils in the allergic lung, suggesting a potential important role for both ligands in the development of asthma. Combined anti-CD80/anti-CD86 treatment throughout the antigen challenge period fully blocked the development of allergic airways, whereas a partial reduction was observed in mice treated with either anti-CD80 or anti-CD86 antibody alone. However, only anti-CD86 blocked systemic IgE production. Therefore, signaling through either CD80 or CD86 is sufficient to generate a partial local allergic response, whereas CD86 costimulation is essential to induce systemic allergic (IgE) reactions. Finally, combined anti-B7 monoclonal antibody treatment after sensitization reduced airway eosinophilia and interleukin (IL)-4/IL-5 cytokine secretion consistent with an ongoing role for CD28/B7 interactions in the effector phase of the disease. These results emphasize the importance of differential B7 expression on different cells and in different organs on subsequent CD28/B7-mediated immune events, including the potential for CD28/B7 blockade in the treatment of atopic airway disease in people.
Am J Respir Cell Mol Biol 1999 Oct
PMID:CD28 interactions with either CD80 or CD86 are sufficient to induce allergic airway inflammation in mice. 1050 60

Dendritic cells (DC) can be present at distinct stages of differentiation within the immune system. Sallusto and colleagues have recently described an in vitro culture system suitable for analyzing the maturation processes of DC (Sallusto and colleagues, J. Exp. Med. 1994;179:1109-1118). Monocytes cultured for 6 d in the presence of granulocyte macrophage colony-stimulating factor and interleukin-4 develop into immature DC with a high endocytic capacity but a low capacity to stimulate T cells. When challenged by lipopolysaccharide, these cells upregulate costimulatory molecules, express CD83, and become mature DC. CCR1 and CCR5 chemokine receptors are highly expressed on immature DC and downregulated on mature DC. This in vitro system was used to characterize human lung DC. Lung DC were shown to express some characteristics of in vitro immature DC. These are: (1) low expression of the costimulatory molecules CD40, CD80, and CD86; (2) poor expression of the differentiation marker CD83 and no CD1a; and (3) good capacity to incorporate dextran. Lung DC express moderate levels of CCR1 and CCR5. However, lung DC, like in vitro mature DC, express high levels of major histocompatibility complex Class II molecules, show low expression of CD14 and CD64, and are characterized by their high capacity to stimulate allogeneic T cells to proliferate during mixed leukocyte reactions (MLRs). Although lung DC express low levels of CD80 and CD86, the important role of these costimulatory molecules in inducing high MLR was demonstrated by using blocking antibodies. Therefore, while lung DC have overall a phenotype and an endocytic capacity close to in vitro immature DC, they share, like in vitro mature DC, a powerful capacity to stimulate T cells.
Am J Respir Cell Mol Biol 1999 Nov
PMID:Human lung dendritic cells have an immature phenotype with efficient mannose receptors. 1053 11


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