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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To futher our understanding of the mechanisms underlying the diverse effects of altered peptide ligands (APL) on T cell activation, we used a population of nonactivated spleen cells from mice that expressed a transgenic TCR specific for myelin basic protein Ac1-11 and peptide analogues that display either enhanced or decreased affinities for TCR/MHC to address the question whether APL-induced signaling through the TCR can regulate the capability of APC to activate T cells. We demonstrate that weak agonists APL are poor inducers of all aspects of the activation of both the responder T cells and the APC. Enhancement of the antigenic signal by augmenting the binding of the weak agonists to MHC reversed their defective activating capacity. Enhancement of costimulation by engagement of CD28 only resulted in augmentation of the capacity of the weak agonist APL to induce proliferation and IL-2/IL-3 production, but not CD40L or IL-12Rbeta2 chain expression on T cells, CD80/CD86 expression on APC, IL-12 secretion, or IFN-gamma production. Exogenous IL-12 promoted IFN-gamma production in the presence of the weak agonists. These studies demonstrate that there is a critical threshold of antigenic signal required for full activation of the T cell-APC interactions needed for the differentiation of Th1 cells. The provision of excess costimulation can overcome some of the defects in T cell activation by weak agonists, but is insufficient to induce a sufficient level of CD40L expression needed for engagement of CD40 on APC with subsequent IL-12 production and induction of IL-12Rbeta2 chain expression.
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PMID:Differential effects of CD28 engagement and IL-12 on T cell activation by altered peptide ligands. 986 89

Endotoxin is physiologically present in portal venous blood at concentrations of 100 pg/ml to 1 ng/ml. Clearance of endotoxin from portal blood occurs through sinusoidal lining cells, i.e., Kupffer cells, and liver sinusoidal endothelial cells (LSEC). We have recently shown that LSEC are fully efficient APCs. Here, we studied the influence of endotoxin on the accessory function of LSEC. Incubation of Ag-presenting LSEC with physiological concentrations of endotoxin lead to >/=80% reduction of the accessory function, measured by release of IFN-gamma from CD4+ T cells. In contrast, conventional APC populations rather showed an increase of the accessory function after endotoxin treatment. Inhibition of the accessory function in LSEC by endotoxin was not due to lack of soluble costimulatory signals, because neither supplemental IL-1beta, IL-2, IFN-gamma, or IL-12 could rescue the accessory function. Ag uptake was not influenced by endotoxin in LSEC. However, we found that endotoxin led to alkalinization of the endosomal/lysomal compartment specifically in LSEC but not in bone marrow macrophages, which indicated that Ag processing, i.e., proteolytic cleavage of protein Ags into peptide fragments, was affected by endotoxin. Furthermore, endotoxin treatment down-regulated surface expression of constitutively expressed MHC class II, CD80, and CD86. In conclusion, it is conceivable that endotoxin does not alter the clearance function of LSEC to remove gut-derived Ags from portal blood but specifically affects Ag processing and expression of the accessory molecules in these cells. Consequently, Ag-specific immune responses by CD4+ T cells are efficiently down-regulated in the hepatic microenvironment.
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PMID:Endotoxin down-regulates T cell activation by antigen-presenting liver sinusoidal endothelial cells. 997 95

N-acetyl-L-cysteine (NAC) is an antioxidant molecule endowed with immunomodulatory properties. To investigate the effect of NAC on the induction phase of T cell responses, we analyzed its action on human dendritic cells (DC) derived from adherent PBMC cultured with IL-4 and granulocyte-macrophage CSF. We first found that NAC inhibited the constitutive as well as the LPS-induced activity of the transcription factor NF-kappaB. In parallel, NAC was shown to down-regulate the production of cytokines by DC as well as their surface expression of HLA-DR, CD86 (B7-2), and CD40 molecules both at the basal state and upon LPS activation. NAC also inhibited DC responses induced by CD40 engagement. The inhibitory effects of NAC were not due to nonspecific toxicity as neither the viability of DC nor their mannose receptor-mediated endocytosis were modified by NAC. Finally, we found that the addition of NAC to MLR between naive T cells and allogeneic DC resulted in a profound inhibition of alloreactive responses, which could be attributed to a defect of DC as APC-independent T cell responses were not inhibited by NAC. Altogether, our results suggest that NAC might impair the generation of primary immune responses in humans through its inhibitory action on DC.
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PMID:N-acetyl-L-cysteine inhibits primary human T cell responses at the dendritic cell level: association with NF-kappaB inhibition. 1007 97

Activation of T cells requires both TCR-specific ligation by direct contact with peptide Ag-MHC complexes and coligation of the B7 family of ligands through CD28/CTLA-4 on the T cell surface. We recently reported that coadministration of CD86 cDNA along with DNA encoding HIV-1 Ags i.m. dramatically increased Ag-specific CTL responses. We investigated whether the bone marrow-derived professional APCs or muscle cells were responsible for the enhancement of CTL responses following CD86 coadministration. Accordingly, we analyzed CTL induction in bone marrow chimeras. These chimeras are capable of generating functional viral-specific CTLs against vaccinia virus and therefore represent a useful model system to study APC/T cell function in vivo. In vaccinated chimeras, we observed that only CD86 + Ag + MHC class I results in 1) detectable CTLs following in vitro restimulation, 2) detectable direct CTLs, 3) enhanced IFN-gamma production in an Ag-specific manner, and 4) dramatic tissue invasion of T cells. These results support that CD86 plays a central role in CTL induction in vivo, enabling non-bone marrow-derived cells to prime CTLs, a property previously associated solely with bone marrow-derived APCs.
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PMID:CD86 (B7-2) can function to drive MHC-restricted antigen-specific CTL responses in vivo. 1009 97

Over the past few years a great deal of research has examined how T cell-dependent immune responses are initiated and subsequently regulated. Ligation of the TCR with an antigenic peptide bound to an MHC protein on a professional APC provides the crucial antigen-specific stimulus required for T cell activation. Interaction of CD28 with CD80 or CD86 molecules on APC initiates a costimulatory or second signal within the T cell which augments and sustains T cell activation initiated through the TCR. However, recently it has become clear that T cell immune responses are a result of a balance between stimulatory and inhibitory signals. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) is a cell surface molecule that is expressed nearly exclusively on CD4+ and CD8+ T cells. Investigation into the role of CTLA-4 in the regulation of T cell immune responses has revealed that CTLA-4 is a very important molecule involved in the maintenance of T cell homeostasis. In the present review, evidence for the proposed inhibitory role of CTLA-4 is examined and a model suggesting a role for CTLA-4 in both early and late stages of T cell activation is presented.
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PMID:The role of CTLA-4 in the regulation of T cell immune responses. 1010 80

Because APCs play a crucial role in the generation of T cell-mediated immune responses, numerous clinical trials with APC-based vaccines have been initiated in different types of human cancers. Encouraging results have emerged from some of these initial studies. Thus far, APC-based vaccinations usually include multiple rounds of immunization. With this approach, although we and others have detected induction of Ag-specific CTL responses in vaccinated patients after stimulation with the same APC-based immunogen, in vitro we also find that repetitive in vitro stimulation with Ag-loaded APC can, at times, lead to the emergence of noncytolytic CD4+ T cells exhibiting the characteristic phenotype of Th2 cells. These noncytolytic CD4+ T cells synthesize large quantities of type 2 cytokines such as IL-4 and IL-10 on stimulation with the autologous APC or tumor cells in an MHC class II-restricted manner. Further, these CD4+ T cells and a cell-free supernatant factor block the activation of fresh T lymphocytes. The supernatant factor also exhibits a marked inhibitory effect on the expression of the costimulatory molecules, CD80 and CD86, by APC. The inhibitory effect of the supernatant factor can be abrogated by neutralizing IL-10 in the supernatant. These observations therefore have implications in the APC-based tumor vaccine protocol design.
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PMID:Emergence of regulatory CD4+ T cell response to repetitive stimulation with antigen-presenting cells in vitro: implications in designing antigen-presenting cell-based tumor vaccines. 1022 40

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 influence of costimulation on the activation of naive CD8+ T cells and thymocytes was studied in vitro using H-Y-specific TCR-transgenic mice and H-Y antigenic peptide. Using a variety of physiological APC types, the activation of naive CD8+ T cells depended strictly on costimulation, which could not be substituted by high epitope density. T cell activation is known to be regulated by the interactions between CD86/CD80 and CD28/CD152, although it remains unclear whether the B7 isoforms have distinct roles. Addition of soluble anti-CD86 Ab led to profound inhibition of T cell reactivity, further confirming the importance of costimulation in naive CD8+ T cell activation. Finally, TCR engagement in the absence of costimulation had no effect on the subsequent reactivity of peripheral naive transgenic CD8+ T cells, but induced nonresponsiveness in mature CD8+ transgenic thymocytes. Collectively, these results demonstrate the importance of costimulation for naive CD8+ T cell activation, suggest that CD80 and CD86 can mediate opposing effects, possibly due to differential interaction with CD152 and CD28, and indicate differences in the sensitivity of immature vs mature CD8+ T cells to the induction of nonresponsiveness following costimulation-deficient Ag presentation.
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PMID:Critical role of costimulation in the activation of naive antigen-specific TCR transgenic CD8+ T cells in vitro. 1041 27

CD154 (CD40 ligand, gp39) interaction with its receptor CD40 has been shown to be critically important for the generation of cell-mediated as well as humoral immunity. It has been proposed that ligation of CD40 on APCs, presumably by activated Th cells, leads to increased APC function as defined by up-regulation of costimulatory molecules and enhancement of IL-12 production. In this report, we directly examined the contribution of the CD154:CD40 pathway in a murine model of allograft rejection. Generation of both the CTL and alloantibody responses following injection with allogeneic P815 tumor cells was severely compromised in CD154 knockout mice and wild-type C57BL/6 mice treated with the anti-CD154 mAb, MR1. Splenic production of IL-2, IFN-gamma, and TNF was significantly suppressed from CD154-deficient mice, indicating a lack of T cell priming. However, splenic cells from CD154 knockout mice induced comparable levels of CD86 expression and IL-12 production when compared with their wild-type littermates. The treatment of CD154-/- mice with the agonistic anti-CD40 mAb, FGK45, generated activated APCs yet failed to restore either the CTL or alloantibody responses to P815. Likewise, immunization with B7-transfected P815 tumor cells failed to generate expansion of the CTL effector population in CD154-/- mice. These results suggest that the generation of allograft immunity is dependent on the interaction of CD154 with CD40 but not primarily for the activation of APCs.
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PMID:Disruption of CD154:CD40 blocks generation of allograft immunity without affecting APC activation. 1045 82

Oral administration of soluble protein Ag induces tolerance, a phenomenon that has hampered mucosal vaccine design. To provoke active immunity, orally administered Ag must be fed together with a mucosal adjuvant such as cholera toxin (CT). Unfortunately, CT is not suitable for clinical use because of its associated toxicity. There is, therefore, a need to develop alternative mucosal immunization regimens. Here we have attempted to alter the intrinsically tolerogenic nature of the intestine and improve immunization potential by expanding and activating intestinal APC in vivo. Previous studies have indicated that intestinal dendritic cells (DC) present oral Ag, but do so in a tolerogenic manner. In the present study we investigated whether DC can be converted from tolerogenic into immunogenic APC by treating mice with Flt3 ligand (Flt3L), a DC growth factor, and then immunizing with CT. We observed increased local and systemic responses to CT in the presence of elevated numbers of intestinal DC. In parallel, CT induced up-regulation of CD80 and CD86 on these Flt3L-expanded DC. In an attempt to develop a toxin-free adjuvant system, we investigated whether IL-1 could be used as an alternative DC-activating stimulus. Using a combination of Flt3L and IL-1alpha, we observed a potent active response to fed soluble Ag, rather than the tolerogenic response normally observed. These data suggest that Flt3L-expanded DC are well positioned to regulate intestinal responses depending on the presence or the absence of inflammatory signals. Flt3L may therefore be a reagent useful for the design of mucosal immunization strategies.
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PMID:Modulating dendritic cells to optimize mucosal immunization protocols. 1049 Sep 61


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