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

The present study examined self-tolerance for T cell receptor (TCR) alpha beta intestinal intraepithelial lymphocytes (iIELs) using the 2C transgenic (Tg) mouse model specific for a peptide antigen (Ag) presented by the class I major histocompatibility complex H-2Ld. Although Tg+ T cells were largely deleted from the periphery of Ag+ mice, equivalent numbers of Tg iIELs were present in Ag+ compared to Ag- mice. Tg iIELs in Ag- mice contained CD8 alpha beta, CD8 alpha alpha, and CD4-CD8- subsets, whereas only CD8 alpha alpha and CD4-CD8- Tg iIEL subsets were detected in Ag+ mice. Analysis of surface markers revealed that Tg iIELs in Ag+ mice expressed decreased levels of Thy-1 and increased CD45R/B220 as compared to Ag- Tg iIELs. In response to activation with exogenous peptide or immobilized anti-TCR mAB, iIELs from Ag- mice proliferated at high levels and produced interleukin (IL)-2 and interferon (IFN)-gamma, while Tg+ iIELs from Ag+ mice proliferated at low levels and failed to produce detectable IL-2 or IFN-gamma. Activation of sorted iIEL subsets from Ag- mice revealed that CD8 alpha alpha and CD4-CD8- subsets produced low levels of IL-2 and IFN-gamma in response to activation with antigen-presenting cells and added peptide or immobilized anti-TCR mAb, while CD8 alpha beta + iIELs responded to endogenous levels of peptide. In response to APC and exogenous peptide, sorted iIEL subsets from Ag+ mice produced IL-2 and IFN-gamma, and proliferated at greatly reduced levels compared to corresponding subsets from Ag- mice. Analysis of cytokine mRNA levels revealed that activation in vitro induced IL-2 mRNA only in Ag-, but not Ag+ iIELs, whereas a high level of IL-4 mRNA induction was detected in Tg+ iIELs from Ag+ mice, and to a lesser degree, from Ag- mice. These data suggest that tolerance for Tg+ iIELs resulted in the deletion of CD8 alpha beta + subsets and the persistence of Tg+ iIEL subsets with decreased sensitivity to endogenous levels of self-peptide. A comparison of the cytokine profiles expressed by Tg+ iIEL subsets in Ag- and Ag+ mice suggested that tolerance induction had involved the functional deviation of cells from TC1 (T helper-1-like) to a less inflammatory TC2 (T helper-2-like) phenotype capable of mediating humoral immune responses in the mucosa.
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PMID:Immune deviation of 2C transgenic intraepithelial lymphocytes in antigen-bearing hosts. 876 Aug 3

We have developed a new expression system based on the E. coli groEL promoter. The suicide vector constructed (called APC vector) allows simultaneous attenuation of a Salmonella strain by disruption of the coding sequence for aroA and stable integration of a gene into the bacterial chromosome. High-level expression of antigen is achieved after Salmonella is taken up by macrophages, a major antigen processing cell of the host. The chloramphenicol acetyltransferase (CAT) and the simian immunodeficiency virus capsid (p27gag) genes were cloned downstream of the groEL promoter and expressed within S. typhimurium. By measuring CAT activity, we showed that the groEL promoter was up-regulated during infection of the J774 macrophage line. The immune response to SIV capsid was assessed in Balb/c mice given one oral dose of vaccine. A local mucosal secretory IgA response against SIV capsid was detected but no systemic antibody response to the same antigen. A systemic CTL response was detected as early as 28 days to as late as 70 days post-immunization. CTL activity was MHC restricted (H-2d) and was mediated by CD3+, CD8+, CD4- T-lymphocytes. These results indicate that with only one oral dose of recombinant Salmonella using the APC vector, a systemic CTL response and a mucosal secretory response against the SIV capsid antigen are elicited in a mouse model.
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PMID:Induction of SIV capsid-specific CTL and mucosal sIgA in mice immunized with a recombinant S. typhimurium aroA mutant. 885 11

We used naive CD4 cells and in vitro-derived Th1 and Th2 effectors from TCR transgenic mice to investigate the requirements of these subsets for TCR signaling and interactions with accessory molecules. Peptide Ag and immobilized anti-CD3 were used to provide different TCR signals. Anti-CD28 Ab or a panel of class II+ fibroblasts, expressing no accessory molecules or expressing intracellular adhesion molecule-1, B7-1, or both molecules, were used as APC or accessory cells (AC). An efficient naive T cell response required a strong TCR signal (high dose anti-CD3 or peptide) and high levels of multiple synergizing costimulatory signals, while effector cells responded efficiently to anti-CD3 alone. Addition of AC only slightly augmented the effector response. Effectors responded to lower doses of peptide than naive cells. However, when peptide-pulsed APC were used to stimulate effectors, requirements varied with the cytokine measured. The production of IL-4 did not require accessory molecules on APC. IL-2 production required interacting APC to express accessory molecules, but was little augmented by AC not presenting Ag, suggesting a requirement for noncostimulatory interactions. Proliferation of effectors closely paralleled IL-2 production. Production of IFN-gamma was intermediate in dependence on accessory molecules, and production of IL-5 was nearly as dependent as IL-2. These results establish major differences between the induction of naive and effector responses and document differential requirements for the induction of distinct cytokines, indicating that different cytokines may be produced depending on the context of effector restimulation.
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PMID:Naive and effector CD4 T cells differ in their requirements for T cell receptor versus costimulatory signals. 2340 Aug 44

The antigen sensitivity of class II MHC restricted human CD4 T-cell clones is demonstrated to increase gradually with time after restimulation. This is manifested in a requirement of less antigen in culture, as well as decreased numbers of peptide-MHC complexes per APC for T-cell activation, and in an increased resistance to inhibition by class II MHC blockade. The increase in antigen sensitivity is accompanied by increased cell-surface expression of CD26, LFA-1, and VLA-1, whereas the expression of TCR and a series of other cell-surface molecules remains unchanged. Using appropriate monoclonal antibodies, we have shown that CD26 and LFA-1 contribute directly to the increased antigen sensitivity of "late-stage" T-cell clones. The late-memory T-cell phenotype established in this study is shown to occur also among T cells activated in vivo. We suggest that increasing the antigen sensitivity via antigen-nonspecific molecules is a physiologic mechanism for maintaining T-cell memory in face of decreasing antigen concentration, and for ensuring preferential activation of memory T cells upon repeated encounter with antigen.
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PMID:Influence of CD26 and integrins on the antigen sensitivity of human memory T cells. 889 31

A quantitative mechanism for the differentiation of CD4 T cells into recognized subsets of Th1 and Th2 effectors is controversial. Here, we define the Ag dose more precisely to the density of a minimal immunogenic peptide presented on the surface of a specific APC type. Th1 and Th2 responder MHC genotypes differ by as much as an order of magnitude in the density of this peptide displayed on B7-2+ B cells. We asked whether such B cells presenting a low ligand density primed Th2 effectors in an MHC genotype with predisposed high-density presentation and Th1-type immunity, and whether high ligand density B cells primed Th1 effectors in an MHC genotype that normally presents a low density and the Th2 phenotype. While low ligand density had the capacity to switch phenotype in the Th1 responder, high-density presentation did not alter genetically determined Th2 responder status.
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PMID:MHC genotype controls the capacity of ligand density to switch T helper (Th)-1/Th-2 priming in vivo. 889 20

T cell adhesion induced after physiological stimulation by antigen was investigated using murine T cell hybridomas specific for a tetanus toxin peptide. By employing a novel assay, the T cell hybridomas were shown to strongly adhere to peptide-pulsed APC in a dose-dependent fashion. Adhesion peaked at 30-60 min and declined thereafter. This assay allowed us to study the relationship between T cell adhesion and later activation responses using tetanus toxin peptide and alanine monosubstituted analogs. We show that the degree of peptide-induced T cell adhesion correlated with the magnitude of late functional responses. CD4, LFA-1 (CD11a/CD18), and CD28 were critical in the adhesion response. The enhancing role of CD4 was further demonstrated by reduced levels of T cell adhesion and late responses of CD4- T cell hybridomas. Reexpression of CD4 reversed these defects. Our data suggest a link between antigen-induced T cell adhesion and late responses and also suggest that signals mediated by TCR and CD4 coengagement may induce a greater activation and/or recruitment of molecules involved in T cell adhesion.
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PMID:Induction of T cell adhesion by antigen stimulation and modulation by the coreceptor CD4. 891 73

We have studied the consequences of invariant chain (Ii) and DM expression on major histocompatibility complex (MHC) class II function. Ii has a number of discrete functions in the biology of class II, including competitive blocking of peptide binding in the endoplasmic reticulum and enhancing localization in the endocytic compartments. DM is thought to act primarily in endosomes to promote dissociation of the Ii-derived (CLIP) peptide from the class II antigen-binding pocket and subsequent peptide loading. In this study, we have evaluated the functional role of Ii and DM by examining their impact on surface expression of epitopes recognized by a large panel of alloreactive T cells. We find most epitopes studied are influenced by both Ii and DM. Most strikingly, we find that surface expression of a significant fraction of peptide-class II complexes is extinguished, rather than enhanced, by DM expression within the APC. The epitopes antagonized by DM do not appear to be specific for CLIP. Finally, we found that DM was also able to extinguish recognition of a defined peptide derived from the internally synthesized H-2Ld protein. Thus, rather than primarily serving in the removal of CLIP, DM may have a more generalized function of editing the array of peptides that are presented by class II. This editing can be either positive or negative, suggesting that DM plays a specifying role in the display of peptides presented to CD4 T cells.
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PMID:Invariant chain and DM edit self-peptide presentation by major histocompatibility complex (MHC) class II molecules. 892 Aug 63

It has long been known that mucosal responses are most effectively stimulated by local presentation of antigen but the mechanisms whereby the gut immune system is able to distinguish between potential pathogens and harmless dietary antigens are not clear. The gut immune system is capable of mounting both primary and secondary responses to potentially harmful antigens while avoiding the expression of damaging responses to harmless food proteins. Historically, most attention has focused on Peyer's patches and there is evidence of their role in the induction of both primary and secondary responses. Fed antigen can also be detected in the intestinal lamina propria (LP) and it has been shown that murine LP cells can stimulate allogenic mixed lymphocyte responses and present KLH to naive T cells. In contrast to guinea pigs, rodents and humans, pig intestinal epithelial cells do not express MHC Class II molecules, but they are present on a number of other cell types in the subepithelial LP. Amongst these are a significant proportion of non-professional APC including endothelial cells and eosinophils. Phenotypically pig LP T cells are a homogeneous population and the majority of CD4 T cells express the low molecular weight isoform of CD45. This is compatible with the suggestion that they are CD45RO-positive cells. A significant proportion of LP CD4 T cells are CD25 (IL-2R) positive, but following activation they secrete IL-4, with little or no IL-2 production. Based upon these observations, we would conclude that the lamina propria is a unique immunological microenvironment, and suggest that it may be of significance not only in surveillance and the provision of help during rapid responses to recall antigens but also in the down-regulation of local responses to food-derived peptides.
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PMID:Antigen presenting cells in the porcine gut. 898 62

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

It is clear by now that cell-to-cell interactions involving a variety of signals are required for effective immune response. The data reviewed here suggest that CD40-CD40L interactions are critical for development of CD4 T-cell-dependent effector functions. Lack of this important interaction results in greatly reduced activation of CD4 T cells, while successful interaction of these molecules results in full activation of these T cells. Consequently, the absence of CD40-CD40L interactions leads to impairment of T-cell effector such as help for B-cell differentiation and class switch, activation of monocytes and macrophages to produce cytokines and to kill intracellular pathogens, and activation of autoreactive T cells to mount an autoimmune response. The effector functions of T cells controlled by CD40-CD40L interactions in a successful immune response are given in Table I. Data presented so far suggest that CD40-CD40L interactions play a role in early signalling events, where interactions of this kind are required to induce expression of costimulatory molecules on APC. One possible sequence of events in that APC, like DC, take up antigens at the site of injury or infection and migrate to lymph nodes, where they present antigens complexed with MHC class II molecules to naive T cells. This results in expression of CD40L on T cells. Coupling of this newly expressed CD40L on T cells with CD40 on APC results in expression of the costimulatory activity of the APC. At this time the costimulatory signal provided by the APC is received by the T cells via CD28/CTLA-4, which drives the cell to enter into cell cycle and complete T cell activation. T cells thereby activated can now enter into secondary cognate CD40-CD40L-dependent effector recognition with B cells to switch Ig class, macrophages to produce cytokines and new DC carrying the same antigen to up-regulate costimulatory activity. A tight regulation of expression of CD40L on T cells and costimulatory activity on APC would prevent activation of unwanted bystander T cells. The coupling of activation of the APC primed with the cognate antigen to the activation of the T-cell specific for that antigen in this model provides an additional regulatory step in the initiation of the immune response. This also suggests that a limited number of T cells/APC will be activated, both of which will be specific in nature. This additional step may be important for safeguarding against an autoimmune response. In addition, the fact that CD40L uniquely seems to play this role suggests that selective immunotherapies to treat autoimmune disease and prevent graft rejection can be targeted on this molecule. On the other hand, CD40-directed approaches to up-regulate costimulatory activity on APC could be developed to fight tumor growth, contain infections and treat immunodeficiencies.
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PMID:The role of CD40 ligand in costimulation and T-cell activation. 901 Jul 20


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