Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dendritic cells (DC) are the major APC in human peripheral blood (PB) and rheumatoid synovium. We previously identified in PB a population of CD33dim-CD14dim DC precursors, as well as a smaller population of CD33bright CD14dim mature DC. Neither PB DC population expressed the CD28/CTLA4 ligands, suggesting that additional signals are required for full functional DC differentiation. Because rheumatoid synovium is characterized by an ongoing immune response, the expression and function of CD80, CD86, and other markers of DC differentiation by rheumatoid arthritis synovial APC were examined. The phenotype of a large subset of freshly isolated rheumatoid arthritis synovial fluid (SF) DC resembled that of the mature PB DC. These DC expressed CD45R0, CD11c, CMRF-44, and high levels of CD33. Whereas CD80 expression by rheumatoid SF DC and monocytes was minimal, CD86 was expressed by a subset of SF monocytes and by CMRF-44+SF DC. Furthermore, sorted CD86- SF DC spontaneously up-regulated CD86 in vitro. CD80 was expressed diffusely and at low levels by rheumatoid synovial tissue cells, whereas CD86 was expressed by perivascular HLA-DR+HLA-DQ+CD80+CMRF-44+ DC, and by some CD14+ monocytes. Anti-CD86 mAb and CTLA4 Ig, but not anti-CD80 mAb, inhibited the MLR stimulated by SF DC. Both CMRF-44+ and CMRF-44- SF DC were efficient stimulators of the allogeneic MLR, which was in each case blocked by CTLA4 Ig. The data indicate that rheumatoid synovial DC can undergo full functional differentiation, associated with CD86 expression, in vitro and in situ. Synovial DC expressing high levels of MHC molecules and CD86 are strategically located to present arthritogenic Ag to T cells after transendothelial migration.
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PMID:Functional differentiation of dendritic cells in rheumatoid arthritis: role of CD86 in the synovium. 860 31

Dendritic cells (DC) are a specific subset of APC characterized by the potent ability to activate immunologically naive T cells. We have observed previously that the murine epidermis-derived DC line XS52 undergoes a set of profound changes upon Ag-specific interaction with T cells, including IL-1 beta secretion acquired expression of CD86, and lost expression of CD115 (CSF-1 receptor) and proliferative responsiveness to CSF-1. These changes, which appear to reflect a critical transition during Ag presentation, have been termed T cell-mediated "terminal maturation" of DC, Here we report that XS52 cells also lose their adhesive and phagocytotic capacities during this event. XS52 cells, ordinarily adhere to petri dishes and phagocytose latex heads, as has been reported for DC freshly procured from spleen and skin. Importantly, XS52 cells lose both capacities after 3 to 24 h of incubation with HDK-1 T cells (keyhole limpet hemocyanin-specific TH1 clone) or with 5S8 T cells (dinitrobenzene sulfonate specific Th0 clone) in the presence of Ag. By contrast, incubation with T cells alone or with Ag alone has minimal effects, indicating that this regulation required both T cells and Ag. With respect to mechanisms, several lines of evidence suggest this IFN-gamma, which is secreted by T cells, serves as the primary mediator in down-regulating both capacities. Our observations illustrate a unique mechanism by which responding T cells upon Ag-specific activation by DC, suppress the machinery of Ag uptake through the elaboration of IFN-gamma.
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PMID:T cell-mediated terminal maturation of dendritic cells: loss of adhesive and phagocytotic capacities. 880 31

To study MHC class II-dependent and -independent SAg2 activation and the relative importance of CD80/CD28 costimulation, staphylococcal enterotoxin A (SEA) was presented to T cells as a fusion protein containing the Fab fragment of an mAb directed against the CA215 glycoprotein. Chinese hamster ovary (CHO) cells transfected with HLA-DR4, CA215, and CD80, individually or in combinations, were used as presenting cells. A strong T cell proliferation was obtained when C215Fab-SEA fusion proteins were presented by CHO-DR/CD80 or CHO-CA215/CD80 double transfectants, whereas only low levels of proliferation were seen in the absence of CD80. Large amounts of IL-2, IFN-gamma, and TNF were produced in addition to an increase in IL-2 mRNA as a result of CD80 costimulation. Only approximately 50% of the SEA-reactive T cells responded by expression of IL-2 receptor chains and by blast formation when activated with SEA in the absence of MHC class II. Reverse transcription-PCR-assisted repertoire analysis of SEA-reactive TCR V beta families showed that the CA215-dependent activation involved an expansion of fewer TCR V beta families compared with MHC class II-dependent activation. One-half of the six analyzed TCR V beta families were expanded independently of class II. This indicates that MHC class II has only a partial influence on the TCR V beta repertoire imprinted by SAg. This finding redefines the role of MHC class II in SAg presentation. It is suggested that MHC class II molecules are selected as SAg-binding molecules mainly as a suitable targeting receptor for professional APC expressing costimulatory molecules such as CD80 and CD86.
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PMID:Regulation of superantigen-induced T cell activation in the absence and the presence of MHC class II. 881 90

Dendritic cells (DC) are the most efficient APC for T cells. The clinical use of DC as vectors for anti-tumor and infectious disease immunotherapy has been limited by their trace levels and accessibility in normal tissue and terminal state of differentiation. In the present study, daily injection of human Flt3 ligand (Flt3L) into mice results in a dramatic numerical increase in cells co-expressing the characteristic DC markers-class II MHC, CD11c, DEC205, and CD86. In contrast, in mice treated with either GM-CSF, GM-CSF plus IL-4, c-kit ligand (c-kitL), or G-CSF, class II+ CD11c+ cells were not significantly increased. Five distinct DC subpopulations were identified in the spleen of Flt3L-treated mice using CD8 alpha and CD11b expression. These cells exhibited veiled and dendritic processes and were as efficient as rare, mature DC isolated from the spleens of untreated mice at presenting allo-Ag or soluble Ag to T cells, or in priming an Ag-specific T cell response in vivo. Dramatic numerical increases in DC were detected in the bone marrow, gastro-intestinal lymphoid tissue (GALT), liver, lymph nodes, lung, peripheral blood, peritoneal cavity, spleen, and thymus. These results suggest that Flt3L could be used to expand the numbers of functionally mature DC in vivo for use in clinical immunotherapy.
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PMID:Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. 892 Aug 82

The aim of this study was to investigate the mechanisms by which B7-related costimulatory molecules (CD80, CD86) increase T-cell responsiveness to extracellular ligands. As a model study, the in vitro response of purified splenic CD4+ T cells to a bacterial superantigen, SEB, was characterized. Previous analysis of this experimental model led us to conclude that expression of B7-related molecules is strictly required in order to activate CD4+ T cells in the presence of bacterial superantigens. In the present report, we demonstrate that antigen-presenting cell-derived costimulatory signals regulate the kinetics of interleukin-2 (IL-2) production by SEB-activated splenic CD4+ T cells. Indeed, experiments performed with purified subpopulations of antigen-presenting cells and using B7-transfected cell lines indicated that increased levels of CD80 and/or CD86 cell surface expression is associated with a faster kinetics of IL-2 production in response to SEB. Accordingly, blocking of CD80 or CD86-derived signals by specific monoclonal antibodies led to a slower kinetics of IL-2 production in response to SEB. Thus these data demonstrate that similar strength of signal through the T-cell receptor can lead to immune responses displaying distinct kinetics depending on the level of costimulatory ligands on APC.
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PMID:Costimulation regulates the kinetics of interleukin-2 response to bacterial superantigens. 894 21

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

In addition to an antigen-specific signal, T cell activation requires an antigen-independent costimulatory signal provided by interaction of CD28 with B7 (CD80 and CD86) on the APC. By blocking B7 interactions, previous studies demonstrated the requirement for costimulation in the induction of experimental allergic encephalomyelitis (EAE). Recent studies suggest that unlike CD28, CTLA-4 (a second B7 ligand) delivers an inhibitory signal. To address the regulatory role of CTLA-4 in EAE, we used an antibody directed against CTLA-4 administered at the time of disease induction. This resulted in a significantly more severe clinical course and more inflammatory and demyelinating lesions in the CNS of anti-CTLA-4-treated mice. These data suggest that CTLA-4-mediated inhibitory signals can regulate the clinical severity and histologic parameters of neuroautoimmune disease.
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PMID:Specific blockade of CTLA-4/B7 interactions results in exacerbated clinical and histologic disease in an actively-induced model of experimental allergic encephalomyelitis. 905 59

Dendritic cells with potent Ag-presenting function can be propagated from peripheral blood using recombinant cytokines, and these cells have potential usefulness as immunotherapeutic agents in the treatment of cancer and other disease states. However, it is not known if these in vitro differentiated dendritic cells have the capacity to migrate in vivo, especially to T cell areas of lymphoid tissue. We have used a fluorescent marker system to track the migration of dendritic cells, propagated in vitro from chimpanzee peripheral blood, following s.c. injection. We report that injected dendritic cells migrate spontaneously and rapidly to draining lymph nodes, where they remain for at least 5 days. The injected cells interdigitate with T cells in the parafollicular and paracortical zones and retain high level expression of CD86, CD40, and MHC class II molecules, reflecting a phenotype of potent APC. We conclude that dendritic cells differentiated in vitro from peripheral blood and administered s.c. behave in a manner very similar to endogenous Langerhans cells. These data provide strong experimental support, in a highly relevant large animal model, for the use of in vitro differentiated dendritic cells as vehicles for immunotherapy. More importantly, they show that the s.c. route of injection delivers these APC to sites of T cell activation, a prerequisite for the generation of an effective immune response.
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PMID:In vivo migration of dendritic cells differentiated in vitro: a chimpanzee model. 914 65

T cell anergy refers to a functional state in which the cells are alive but unable to produce IL-2 after appropriate triggering. Lack of CD28 costimulation through CD80 and CD86 molecules on APC might play a causative role in anergy induction, as previously shown with T cell clones. We now developed a model of anergy induction in cultures of freshly isolated memory T cells. Addition of either CTLA-4Ig or blocking anti-CD80 and anti-CD86 mAbs, in combination with cyclosporin A, to cultures of PBMC with soluble Ag consistently resulted in Ag-specific unresponsiveness, as evidenced upon antigenic rechallenge. In most experiments, the presence of cyclosporin A was not required, and blocking the B7-CD28 interaction during antigenic stimulation was sufficient to induce unresponsiveness. Unresponsiveness was apparent at the level of T cell proliferation as well as at the level of IL-2 and IFN-gamma production, and T cell responses to unrelated Ags were intact. Induction of unresponsiveness correlated with lack of T cell proliferation in the induction culture and could largely be prevented by supplementing the induction cultures with rIL-2, indicating that lack of IL-2 was responsible for this altered functional state. Unresponsive T cells did not suppress the proliferation of autologous T cells in response to original or third-party Ags. On the other hand, culture with IL-2 and Ag could reverse established T cell unresponsiveness, pointing to anergy rather than deletion as the underlying mechanism. Anergy induction in freshly isolated memory T cells opens perspectives for treatment of autoimmune and allergic diseases.
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PMID:B7-blocking agents, alone or in combination with cyclosporin A, induce antigen-specific anergy of human memory T cells. 914 87

Transforming growth factor-beta 1 (TGF-beta 1) is a cytokine with complex immunomodulatory effects including the ability to inhibit the onset or severity of autoimmune disease. This study was designed to test the possibility that one mechanism by which TGF-beta 1 exerts its immunosuppressive effects is by inducing antigen (Ag)-specific unresponsiveness in CD4+ cells. TGF-beta 1 was shown here to inhibit the Ag-specific proliferation of naive CD4+ cells from T cell receptor (TCR) transgenic mice. More importantly, the naive CD4+ cells exposed to TGF-beta 1 and Ag, but not to TGF-beta 1 alone, in primary cultures were unable to proliferate or secrete IL-2 in response to a subsequent Ag challenge following removal of TGF-beta 1 from the cultures. Anti-CD28 mAb partially blocked the Ag-specific inactivation induced by TGF-beta 1 in naive CD4+ cells. The inhibitory effects of TGF-beta 1 on CD4+ cells are not mediated by alterations in APC costimulation since TGF-beta 1 did not inhibit the Ag-induced expression of MHC class II molecules, CD80 or CD86 on splenic APC. Taken together, the results suggest that the immunosuppressive activities of TGF-beta 1 encompass direct induction of Ag-specific unresponsiveness in naive CD4+ cells.
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PMID:Transforming growth factor-beta 1 induces antigen-specific unresponsiveness in naive T cells. 924 66


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