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)

The interaction of the T cell surface protein CD28 with its ligand, B7-1 or B7-2, provides a critical costimulatory signal for T cell activation. T cells from CD28- mice are deficient in a variety of responses, including those to lectins and allogeneic spleen cells. However, some immune responses do occur in CD28- mice, suggesting the existence of alternate costimulatory pathways. In this work, we show that T cells purified from CD28- mice respond to B lymphomas expressing 4-1BB ligand (4-1BBL), a member of the TNF gene family. This response is inhibited by a soluble form of 4-1BB, the T cell surface receptor for 4-1BBL. Thus, 4-1BBL/4-1BB interaction provides costimulatory signals to T cells independent of signaling through the CD28 receptor. We find that 4-1BBL is inducible on splenic B cells by CD40 ligand/CD40 interaction or by culturing of splenic dendritic cells, treatments that also induce B7 family molecules. CD28- T cells fail to respond in an MLR to resting allogeneic spleen cells. However, treatment of spleen cells with CD40 ligand renders them competent in activation of CD28- T cells. In contrast to results using B lymphomas as APC, soluble 4-1BB fails to inhibit the T cell response to activated spleen cells. This failure of soluble 4-1BB to block an MLR between CD28+ or CD28- T cells and allogeneic spleen cells is in contrast to a previous report with CD28+ cells.
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PMID:Costimulation of CD28- T lymphocytes by 4-1BB ligand. 899 67

Previous studies on human Th subset development were restricted to the analysis of naive T cells activated with anti-CD3 mAb in the absence of physiologic APC. In this study, we have analyzed the role of cytokines and physiologic APC on T cell maturation in an Ag-specific system, in which naive neonatal CD4 T cells were primed with allogeneic dendritic cells (DC). We found that the cytokine profile of primed cells was dependent upon 1) the ratio between T cells and allogeneic DC and 2) the endogenous production of IL-4 and IL-12. Neutralization of IL-4 during primary MLR increased IFN-gamma production at priming and shifted the phenotype of primed cells from Th0 to Th1. These effects were IL-12 dependent, in that they were suppressed by anti-IL-12 Abs. The production of IL-12 in primary MLR was further evidenced by the presence of IL-12 p40 in the culture supernatant fluids. IL-12 production was suppressed by exogenous IL-4 and increased by anti-IL-4 blocking mAbs, indicating that endogenous IL-4 down-regulated IL-12 production by DC. Finally, IL-12 was produced as a result of T cell/DC interaction involving the CD40/CD40 ligand and CD28/B7 costimulation pathways, as revealed by the inhibitory effect of anti-CD40 ligand mAb and CTLA-4Ig. These observations suggest that in neutral conditions, Ag presentation by DC results in the coordinate production of naive T cell-derived IL-4 and DC-derived IL-12 that in concert shape the cytokine profile of Th cells.
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PMID:T cell-derived IL-4 and dendritic cell-derived IL-12 regulate the lymphokine-producing phenotype of alloantigen-primed naive human CD4 T cells. 899 77

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

Recent data suggest that CD40 ligand (CD40L)-CD40 interactions are essential for up-regulation of costimulatory activity on APC and that efficient induction of CD40L may be pivotal to the success of a CD4 T cell response. CD40L is regulated primarily by TCR signaling, but high level expression on a naive T cell appears to require additional interactions between T cell coreceptors and APC accessory molecules. The data reported here show that resting B cells presenting peptide Ag, in contrast to both dendritic cells and preactivated B cells, induce very little CD40L on naive CD4 cells, which in turn is insufficient to promote APC costimulatory activity. We also show, however, that previously activated effector T cells have enhanced responsiveness to Ag when accessory molecule help is limiting and consequently can express high levels of CD40L after interaction with resting B cells. High level CD40L expression correlated with B cell activation and up-regulation of costimulatory activity; however, blocking studies showed that CD40L was only partially responsible for these phenomena. These studies reinforce the notion that resting B cells may be tolerogenic for naive CD4 cells in part because of inefficient CD40L induction. The data also suggest that a successful primary T cell response will only occur if either the initial interaction is with a dendritic cell followed by subsequent interactions of the effector T cells with resting APC or if nonspecific inflammatory stimuli up-regulate accessory molecule expression on resting APC before an encounter with the naive T cell.
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PMID:CD40 ligand induction on T cell subsets by peptide-presenting B cells: implications for development of the primary T and B cell response. 927 17

Tolerance is thought to occur when Ag is presented to T cells in the absence of costimulatory interactions from APC accessory molecules. Of the professional APC, the resting B cell may be the main tolerizing cell in vivo. We have analyzed several aspects of activation of naive transgenic CD4 cells stimulated with resting or activated B cells presenting peptide Ag. Similar results were obtained with stimulation from peptide presenting fibroblast APC lacking or expressing B7-1 with intracellular adhesion molecule-1. TCR ligation with little or no accessory molecule coreceptor engagement induced efficient blastogenesis; up-regulation of CD25, CD44, CD69, CD95 and CD71; and down-regulation of CD62L over a 48-h period. Accessory molecule help enhanced the expression of CD25, CD44, CD69, and CD71, but to very modest degrees. Only two molecules, CD40 ligand and IL-2, were found to be extremely dependent on accessory molecule help, with little or no expression evident with peptide presented on resting B cells or class II-positive fibroblasts. T cells induced on resting B cells expanded minimally over 3 days, and this was followed by extensive cell death and hyporesponsiveness of the resulting cells. These studies suggest that under tolerizing conditions, such as Ag presentation by resting B cells, much of the naive CD4 response is induced efficiently. Partial activation, however, may be the overall result due to the lack of CD40 ligand expression, which may regulate costimulatory activity in APC and, in turn, may contribute to limiting the production of IL-2 required for T cell expansion and survival.
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PMID:Partial activation of naive CD4 T cells and tolerance induction in response to peptide presented by resting B cells. 931 24

IL-12 is a heterodimeric cytokine produced by APC that promotes the development of CD4+ Th1 cells and their IFN-gamma production after TCR/CD3 triggering. We here investigated the capacity of IL-12 to modify the expression on T cells of CD40 ligand (CD40L or CD154), a molecule transiently expressed on activated T cells and known to be of utmost importance for cognate interaction with B cells and for activation of dendritic cells and macrophages. Our data demonstrate that IL-12 up-regulates CD40L expression on anti-CD3-activated human peripheral blood T cells. For optimal induction of CD40L, IL-12 synergizes with IL-2 as well as with other costimulatory interactions, such as B7/CD28. The effect of IL-12 was observed at both the protein and the mRNA level. T cells costimulated by IL-12 provided more efficient help for IL-4-dependent B cell proliferation and for IgG production than when activated in the absence of IL-12. This helper activity was blocked by an mAb against CD40L, indicating that the effect of IL-12 on B cells is mediated indirectly through CD40L. The data thus suggest that the effects of IL-12 on cellular and humoral immune responses are partly mediated through CD40L induction.
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PMID:IL-12 up-regulates CD40 ligand (CD154) expression on human T cells. 957 May 30

Bone marrow-derived dendritic cells (BmDC) are potent APC and can promote antitumor immunity in mice when pulsed with tumor Ag. This study aimed to define the culture conditions and maturation stages of BmDC that enable them to optimally function as APC in vivo. BmDC cultured under various conditions (granulocyte-macrophage CSF (GM-CSF) or GM-CSF plus IL-4 alone or in combination with Flt3 ligand, TNF-alpha, LPS, or CD40 ligand (CD40L)) were analyzed morphologically, phenotypically, and functionally and were tested for their ability to promote prophylactic and/or therapeutic antitumor immunity. Each of the culture conditions generated typical BmDC. Whereas cells cultured in GM-CSF alone were functionally immature, cells incubated with CD40L or LPS were mature BmDC, as evident by morphology, capacity to internalize Ag, migration into regional lymph nodes, IL-12 secretion, and alloantigen or peptide Ag presentation in vitro. The remaining cultures exhibited intermediate dendritic cell maturation. The in vivo Ag-presenting capacity of BmDC was compared with respect to induction of both protective tumor immunity and immunotherapy of established tumors, using the poorly immunogenic squamous cell carcinoma, KLN205. In correspondence to their maturation stage, BmDC cultured in the presence of CD40L exhibited the most potent immunostimulatory effects. In general, although not entirely, the capacity of BmDC to induce an antitumor immune response in vivo correlated to their degree of maturation. The present data support the clinical use of mature, rather than immature, tumor Ag-pulsed dendritic cells as cancer vaccines and identifies CD40L as a potent stimulus to enhance their in vivo Ag-presenting capacity.
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PMID:Generation of tumor immunity by bone marrow-derived dendritic cells correlates with dendritic cell maturation stage. 988 83

Bioactive IL-12 is composed of two subunits, p35 and p40. In the APC-Th cell interaction, p40 mRNA accumulation in APC was shown to be up-regulated by stimulation with CD40 ligand (CD40L) on Th cells. However, the CD40-CD40L interaction scarcely induced p35 mRNA accumulation in APC. In the present experiments, p35 mRNA accumulation was induced in splenic macrophages/dendritic cells by the interaction with paraformaldehyde-fixed Th1 cells in the presence of Ag, and the p35 mRNA accumulation was abrogated by the inclusion of anti-I-A in cultures to block TCR/MHC class II interaction. The accumulation was also induced by the stimulation with agonistic anti-I-A. These results indicate that the interaction of the MHC class II molecule with TCR evokes an activation signal for p35 mRNA accumulation in APC. Furthermore, the production of bioactive IL-12 in macrophages/dendritic cells stimulated with CD40L was enhanced by the inclusion of agonistic anti-I-A. The p35 mRNA accumulation and IL-12 production of macrophages/dendritic cells induced by stimulation with OVA-specific fixed Th1 clone expressing CD40L were also enhanced by adding OVA in cultures. These results indicate that the p35 mRNA accumulation induced by MHC class II stimulation plays a role in bioactive IL-12 production.
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PMID:Effective stimulation for IL-12 p35 mRNA accumulation and bioactive IL-12 production of antigen-presenting cells interacted with Th cells. 1035 57

Because dendritic cells (DC) play a major role in the initiation of T cell-mediated immunity, we studied the effects of glucocorticoids, well-known inhibitors of the immune and inflammatory response, on the differentiation and maturation of human DC. DC were differentiated from human monocytes by culture with GM-CSF and IL-4 for 7 days with and without dexamethasone (Dex). Cells treated with Dex (10-8 M) (Dex-DC) developed a characteristic dendritic morphology; however, membrane phenotype analysis demonstrated that they were not fully differentiated. Dex-DC expressed low levels of CD1a and, unlike untreated cells, high levels of CD14 and CD16. Molecules involved in Ag presentation (CD40, CD86, CD54) were also impaired. In contrast, molecules involved in Ag uptake (mannose receptor, CD32) and cell adhesion (CD11/CD18, CD54) were up-regulated. After exposure to TNF-alpha or CD40 ligand, Dex-DC expressed lower levels of CD83 and CD86 than untreated cells. Dex-DC showed a higher endocytic activity, a lower APC function, and a lower capacity to secrete cytokines than untreated cells. Overall, these results indicate that DC differentiated in the presence of Dex are at a more immature stage. Moreover, Dex also partially blocked terminal maturation of already differentiated DC. In conclusion, our data suggest that glucocorticoids may act at the very first step of the immune response by modulating DC differentiation, maturation, and function.
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PMID:Glucocorticoids affect human dendritic cell differentiation and maturation. 1035 62

The balance between Th1 and Th2 development is determined by IL-4 and IL-12. While the role for CD4+ NK1.1+ T (NKT) cells in influencing this balance has been recognized based on their capacity to produce IL-4, it is unknown how IL-12 is produced in the innate immune system in which they participate. This study demonstrates that Ag-activated CD4+ NKT cells express CD40 ligand (CD40L) (CD154), which engages CD40 on APC and stimulates them to produce IL-12. Culture of B cell-depleted spleen cells from C57BL/6 mice with alpha-galactosylceramide (alpha-GalCer) capable of selectively stimulating Valpha14/Jalpha281+ NKT cells resulted in the production of IL-12 together with IFN-gamma and IL-4. alpha-GalCer-induced IL-12 production occurred in I-Abbeta-deficient mice, but not in beta2-microglobulin-deficient and Valpha14/Jalpha281 TCR-deficient mice, and was inhibited by anti-CD40L mAb. Of CD4+ and CD4- NKT cells, the capacity to express CD40L/CD154 and trigger IL-12 production following alpha-GalCer stimulation was exhibited preferentially by the CD4+ NKT subset. IL-12 production was also observed in alpha-GalCer-treated mice. Production of IL-12 preceded IFN-gamma production, and IL-12 was required for IFN-gamma, but not IL-4, production. A stimulatory/inhibitory relationship existed between IL-12 and IL-4 production. These results illustrate a novel function of CD4+ NKT cells that could be involved in the regulation of Th1 vs Th2 development.
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PMID:A novel function of Valpha14+CD4+NKT cells: stimulation of IL-12 production by antigen-presenting cells in the innate immune system. 1038 4


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