Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The capacity of human peripheral blood (PB) dendritic cells (DC) and monocytes to facilitate T cell activation and the interaction molecules employed were compared. We have shown that precursors of DC constitute 2 to 3% of circulating PBMC, and can be isolated as CD33+CD14dim cells, whereas monocytes are CD33+CD14bright. Freshly obtained DC expressed similar densities of HLA-DR and the accessory molecules LFA-3, ICAM-1, and B7 as monocytes; after a 36-h incubation the expression of HLA-DR, ICAM-1, and B7 increased on both APC. Accessory cell function was examined in PB T cell cultures stimulated by suboptimal concentrations of immobilized mAb to CD3, and by stimulation of an allospecific T cell line. Freshly isolated monocytes and DC were comparable accessory cells in these assays, but their accessory function was increased by in vitro preincubation, although cultured DC and monocytes were comparably active. In contrast, DC were much more effective stimulators of freshly isolated allogeneic T cells than monocytes. DC were much more effective stimulators of freshly isolated allogeneic PB CD4+ naive and memory T cells than monocytes, whereas DC and monocytes were comparable accessory cells for memory and naive T cells stimulated with immobilized anti-CD3. The accessory molecules ICAM-1, LFA-3, and B7 were used comparably by DC and monocytes for accessory function in the presence of immobilized anti-CD3 and in the MLR, and none was unique for either APC population. These accessory molecules costimulated T cells in an additive fashion. Although immature blood DC and monocytes expressed minimal B7 and did not utilize it as an accessory molecule, B7 played an important role in the increased accessory function of differentiated APC. The results indicate that PB DC and monocytes function most efficiently after differentiation into mature cells that express increased amounts of MHC and other accessory molecules. Because DC and monocytes exhibit comparable accessory function in anti-CD3 T cell stimulation, differences in the expression of MHC molecules and/or their bound peptides are likely to explain the markedly enhanced capacity of DC to stimulate allogeneic PB T cells.
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PMID:Comparative accessory cell function of human peripheral blood dendritic cells and monocytes. 825 94

Little is known regarding the identification, classification, and function of class II MHC+ dendritic cells in the perivasculature of human connective tissues, such as the dermis. We developed a method for preparing papillary dermal cell suspensions from human keratome strips. Among the class II MHC+ populations of the dermis identified using triple color flow cytometry, cells of monocyte/macrophage lineage (CD45+ CD1- CD11b+ CD11clo-mid CD32+ CD36+ or - CD11a-) and mesenchymal cells of non-bone marrow origin (CD45-) were identified and characterized. Another distinct class II MHC+ subset was identified, which expressed a number of features analogous to epidermal Langerhans cells (LC) and other dendritic APC. These were a numerically minor population comprising only 2.7% +/- 1% (n = 7) of dermal cells. Like LC, they express HLA-DR, CD45, CD1a (albeit at a lower level of expression), CD1c, and CD32 and lack constitutive CD11a or ICAM-1. In contrast to LC, this dermal CD1a+CD1c+ subset expresses CD1b, CD11b, a higher level of CD11c, and intracytoplasmic factor XIIIa. Alloantigen presentation by unfractionated dermal cells was reduced by prior removal of this CD1b+ subset to the same degree achieved by removal of the entire DR+ population (20% of dermal cells), indicating that this was the critical DR+ subset. Cocultures of CD4+ T lymphocytes with cells sorted by flow cytometry into CD1c+DR+, CD1c-DR+ and DR- dermal cell subsets positively identified the CD1c+DR+ population as the most potent of potential APC subsets in human dermis. Thus, in distinction to other dermal macrophage and mesenchymal subsets with elongate morphology, the CD1aloCD1b,c+CD11c(hi)CD11b+CD32+DR+ population in human dermis is highly analogous to cells of LC/dendritic APC lineage in its phenotype and in its exclusive ability to potently present Ag to T lymphocytes. These studies identify and characterize the APC subset most potent in inducing activation of T cells initially entering the perivasculature of human dermis to be of LC/dendritic APC, and not tissue macrophage, lineage.
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PMID:Heterogeneous populations of class II MHC+ cells in human dermal cell suspensions. Identification of a small subset responsible for potent dermal antigen-presenting cell activity with features analogous to Langerhans cells. 840 86

The CD40 ligand (CD40L):CD40 interaction plays an important role in the activation of both T and B cells. However, the mechanisms by which this interaction is involved in activation of T cells is still unclear. Here we show that CD40L is not essential for T cell response to TCR engagement if the APC have costimulatory activity, although it is essential for T cell-mediated induction of such costimulatory activity. To determine the molecular basis of this activity, we have produced three mAbs that appear to recognize the costimulatory molecules rapidly induced by CD40L. Two of them recognize CD44H, which we showed to have CD28-independent costimulatory activity for T cells. The molecule recognized by the remaining mAb is hereby identified as ICAM-1. Furthermore, ICAM-1-mediated costimulation is likely to serve for a function similar to that mediated by the B7:CD28 interaction, as targeted mutation of CD28 renders T cell responses to Con A more dependent on ICAM-1.
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PMID:CD40L is important for induction of, but not response to, costimulatory activity. ICAM-1 as the second costimulatory molecule rapidly up-regulated by CD40L. 881 78

Two signals are required for induction of cell proliferation and cytokine production in resting T cells. Occupancy of the T cell receptor by antigen/MHC complexes delivers the first signal to the T cell, while the second signal is provided by interaction with costimulatory ligands on APC. CD2, LFA-1, and CD28 are the major costimulatory and adhesive molecules on T cells and bind to the LFA-3, ICAM-1 and B7 ligands, respectively, on APC. LFA-3 plays a central role for naive and memory T helper cells during the early phase of an immune response. The LFA-3/CD2 pathway initiates strong antigen-independent cell adhesion, substantial expansion of naive T helper cells, and induction of large amounts of IFN-gamma in memory cells. The release of IFN-gamma may upregulate expression of ICAM-1 and B7 on APC and allows multiple adhesion pathways to amplify the immune response. The LFA-1/ICAM-1 pathway stimulates adhesion and cell proliferation more efficiently in memory T helper cells than in naive cells. Further, the results suggest that naive T helper cells express functionally inactive LFA-1 molecules on the cell surface, which may have a physiological role in keeping these cells in a resting state. B7 costimulation superinduces IL-2 production in both naive and memory T helper cells and generates long-lasting cell proliferation. This permits transition from an autocrine to a paracrine immune response. Coexpression of B7/LFA-3 provides an optimal APC function and enables a vigorous T cell response to minute amounts of antigen. AP-1 and NF-kappa B transcription factors are involved in the induction of several cytokine gene promoters and play a central role in the regulation of IL-2 gene transcription. LFA-3 costimulation only moderately enhances AP-1 DNA-binding activity and does not influence the NF-kappa B activity induced by TCR engagement, whereas B7 costimulation induces large amounts of NF-kappa B and AP-1 activity in T helper cells. The costimulatory ligands represent a family of adhesion molecules with considerable redundancy. Interfamily redundancy of LFA-3, B7, and ICAM ligands offers an opportunity to regulate distinct T cell response profiles in various microenvironments at separate time points of an immune response.
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PMID:T cell activation pathways: B7, LFA-3, and ICAM-1 shape unique T cell profiles. 883 50

Molecular alterations play a key role in the pathogenesis of gastrointestinal cancers. In the present paper we describe relevant molecular alterations in human pancreatic adenocarcinomas. Overexpression of growth factor receptors (EGF receptor, c-erbB2, c-erbB3, TGF beta receptor I-III), growth factors (EGF, TGF alpha, TGF beta-1-3, aFGF, bFGF), adhesion molecules (ICAM-1, ELAM-1) and gene mutations (p53, K-ras, DCC, APC) are present in a significant number of these tumors. These changes stimulate tumor growth and enhance the metastatic behavior of pancreatic cancer cells and thereby may contribute to shorter postoperative survival following tumor resection.
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PMID:Pancreatic cancer: the potential clinical relevance of alterations in growth factors and their receptors. 883 68

Dendritic cells (DC) are potent APC that, in mature form, can be distinguished from other mononuclear cells on the basis of their distinct morphology, absence of lineage markers, and dense expression of MHC and costimulatory molecules. While comparing different DC preparation methods, we observed that DC derived from cultured PBMC that had been depleted of CD2+ cells before culture were functionally distinct from DC derived from PBMC that had not been depleted of CD2+ cells. Thus, both types of DC stimulated allogeneic T cells to proliferate in the MLR, but only DC derived from CD2+ precursors could sensitize naive T cells to soluble Ags such as keyhole limpet hemocyanin and HIV gp160 glycoprotein. Subsequent studies confirmed the existence of CD2+ and CD2- DC precursor populations among HLA-DRbright, lineage-negative PBMC. Immediately after their isolation, these populations were morphologically similar to one another by light and electron microscopy, and neither had substantial Ag-presenting activity. After culture for 24 to 48 h with supernatant from PHA-activated PBMC, both populations developed dendrites, formed clusters with T cells, and stimulated allogeneic T cell responses in the MLR as well as autologous T cell responses to tetanus toxoid, a recall Ag. However, CD2+ DC precursors alone gave rise to APC that presented soluble Ags to naive CD4+ T cells, a property that could be inhibited by Abs to CD4, CD11a, and CD28 on T cells or CD86 on DC. The expression of CD54 and CD86 on CD2+ DC precursors was increased markedly after their culture and differentiation, while the expression of these molecules on CD2- DC precursors was not remarkably changed. These findings reveal the existence of two functionally distinct populations of DC, each derived from a phenotypically distinct precursor present in monocyte-depleted peripheral blood.
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PMID:Dendritic cells that process and present nominal antigens to naive T lymphocytes are derived from CD2+ precursors. 903 58

CD40 ligand (CD40L) expression on T cells is known to play a crucial role in B cell responses. Some evidence also supports a role for CD40L-CD40 interactions in T cell responses, at least in vivo. Whether the T cell requirement for these interactions is an invariable finding, however, is less clear. Here, we provide evidence that the Ag specificity of T cells influences the requirement for CD40L. T cell hybridomas with dual reactivity for two different Ags, allo-H2-Ap and Mls(a) superantigens, display a differential requirement for CD40L expression. Whereas the response to splenic APC expressing Mls(a) Ags requires CD40L expression, the response to alloantigen-bearing APC does not. The requirement for CD40L expression for the Mls(a) response appears to reflect a strong dependence of this response on ICAM-1 (intercellular adhesion molecule-1) and the ability of CD40-mediated signals to regulate ICAM-1 expression. These findings demonstrate that CD40L-CD40-mediated cross-talk is important for some but not all T cell responses and is influenced by both the type of Ag recognized and the type of APC.
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PMID:Antigen specificity of dual reactive T hybridomas determines the requirement for CD40 ligand-CD40 interactions. 920 Apr 57

Dendritic cells (DC) play an essential role in the initiation of primary T cell responses to foreign Ag. It is likely that these potent APC are critical in the initiation of immune responses to pathogens, such as bacteria or parasites. However, little is known about the interaction of these important APC with pathogens. To address this issue, the interaction of the bacterium Mycobacterium tuberculosis with human DC was studied. DC generated from human peripheral blood by short term culture in medium containing recombinant human cytokines granulocyte-macrophage-CSF and IL-4 were capable of phagocytosing M. tuberculosis. Infection of DC with live M. tuberculosis bacilli resulted in increased APC surface expression of the costimulatory molecules CD54, CD40, and B7.1, as well as MHC class I molecules. In addition, infected DC secreted elevated levels of inflammatory cytokines, including TNF-alpha, IL-1, and IL-12. M. tuberculosis-infected human monocytes also secreted inflammatory cytokines, but exhibited no enhancement of costimulatory or MHC class I molecule expression. These data indicate that infection with M. tuberculosis results in the direct activation and maturation of these DC. In vivo, such activation may facilitate migration to the lymph nodes, and enhance presentation of Ag to T cells, thereby facilitating the induction of the immune response against this pathogen.
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PMID:Activation of human dendritic cells following infection with Mycobacterium tuberculosis. 921 78

OX40 ligand (OX40L), a member of the TNF family, was shown to be capable of signaling both the cells on which it is expressed and those expressing OX40, its cognate receptor. Here we show that OX40L is expressed on dendritic cells (DC), the most efficient APC to prime naive T cells. The expression and the functional activity of OX40L were examined by means of mAbs used to stain or cross-link OX40L on 1) freshly isolated human blood DC (bDC) and 2) monocyte-derived DC at different stages of differentiation. These were derived from monocytes cultured either with IL-4 and granulocyte-macrophage CSF (IL-4-Mo-DC) or with IL-4 and granulocyte-macrophage CSF plus TNF-alpha. Both types of Mo-DC expressed OX40L after stimulation through CD40; ligation of OX40L on activated IL-4-Mo-DC enhanced by 4- to 35-fold their cytokine production (TNF-alpha, IL-12 p40, IL-1 beta, and IL-6) and increased CD80, CD86, CD54, and CD40 expression. Stimulation of activated IL-4-Mo-DC through OX40L strikingly enhanced their maturation as evidenced by CD83 up-regulation, CD115 (CSF-1R) down-regulation, and typical morphologic changes. OX40L was constitutively expressed on a subset of bDC, and its ligation slightly enhanced CD40L-stimulated IL-12 production. OX40L was down-regulated after overnight culture and spontaneously reexpressed on a subset of mature bDC (CD83high, CD33high, CD11chigh, CD5+). Thus, the expression of OX40L on DC suggests a physiologic role of this molecule during T cell priming by virtue of its ability to costimulate both T cell and DC activation and differentiation.
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PMID:Expression and function of OX40 ligand on human dendritic cells. 937 71

We describe a subset of peripheral CD14+ cells, coexpressing the CD34 progenitor marker and able to migrate across endothelial cell monolayers. On culture with granulocyte-macrophage-CSF, this population differentiated into dendritic cells expressing CD83, CD80, HLA-DR(bright), CD86, and CD54. These dendritic cells were immunostimulatory, in that they induced proliferation of allogenic and tetanus toxoid-specific T lymphocytes. The CD14+ CD34+ population expressed higher levels of platelet endothelial cell adhesion molecule-1 (PECAM-1) and alpha4beta1 integrin than the CD14+ CD34- counterpart, being dull positive for other integrins. Using stably transfected PECAM-1+, VCAM-1+, or ICAM-1+ cells, we found that PECAM-1 and, to a lesser extent, VCAM-1, could support transmigration of CD14+ CD34+ cells, whereas the alphaL-ICAM-1 interaction was involved in cell adhesion. PECAM-1-driven transmigration was conceivably dependent on a haptotactic gradient, as it was reduced by 80% across NIH3T3 cells transfected with the PECAM-1-delta cyto deletion mutant. This mutant lacks the cytoplasmic tail and displays a reduced tendency to localize at the intercellular junctions, thus failing to form a molecular junctional gradient. Once differentiated, dendritic cells derived from CD14+ CD34+ precursors retained their transendothelial migratory capability, using both PECAM-1 and ICAM-1 for transmigration. We suggest that a subset of CD14+ CD34+ circulating leukocytes can localize to peripheral tissues and differentiate into functional dendritic cells, thus representing a functional reservoir of potential APC. PECAM-1, constitutively expressed on vascular endothelium, is likely to play a relevant role in the egress of this population from the bloodstream.
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PMID:CD14+ CD34+ peripheral blood mononuclear cells migrate across endothelium and give rise to immunostimulatory dendritic cells. 951 Jan 66


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