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)

Eight representative T lymphocyte clones (TLC) randomly selected from previously described panels of CD4+ housedust mite Dermatophagoides pteronyssinus (Dp)-specific TLC from atopic and nonatopic donors were studied in more detail in a comparative investigation. The TLC from the atopic donors closely resembled murine type 2 Th (Th2) cells by secreting substantial IL-4, IL-5, IL-6, TNF-alpha, and granulocyte-macrophage (GM)-CSF, minimal IFN-gamma, and relatively little IL-2. In contrast, the nonatopic's TLC resembled murine type 1 Th (TH1) cells by secreting substantial IFN-gamma, IL-2, TNF-alpha, and GM-CSF, no IL-4, and little IL-5. A difference with murine Th1 cells was their additional secretion of IL-6. These cytokine profiles were consistent upon stimulation via different activation pathways including stimulation with specific Dp Ag, mitogenic lectins, and antibodies to CD2, CD3, or CD28. The observed differences in IL-2 secretion, however, were most evident upon stimulation with anti-CD28. If TLC cells were cultured with highly purified B cells and stimulated with anti-CD3 in the absence of exogenous IL-4, IgE synthesis was induced only in cultures with the atopics' Th2 clones, which could be completely abrogated by anti-IL-4. The mere presence of exogenous rIL-4, however, did not result in IgE synthesis, nor did unstimulated TLC cells alone. But if unstimulated TLC cells (that proved not to secrete detectable amounts of cytokines) were added together with rIL-4, again IgE synthesis was induced only in cultures with the atopics' Th2 clones, suggesting the involvement of an additional, as yet unidentified accessory helper function of the atopics' Th2 clones for IgE induction. Unstimulated Th2 clones showed a significantly higher expression of CD28 than the Th1 clones, but three days after stimulation, CD28 expression was elevated to comparable levels on both subsets. When added to B cells at this time point, together with rIL-4 and anti-IFN-gamma, still only the atopics' Th2 clones supported IgE synthesis, arguing against a role for CD28 in this accessory helper function. Whereas the atopics' Th2 clones were excellent helper cells for IgE induction, a unique property of the nonatopic's Th1 clones was their cytolytic activity toward autologous APC which could be induced by specific Dp Ag and by anti-CD3. The present data provide clear evidence for the existence of Th1 and Th2 cells in man.
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PMID:Human atopen-specific types 1 and 2 T helper cell clones. 168 Sep 23

A cytokine synthesis inhibitory factor (CSIF) is secreted by Th2 clones in response to Con A or antigen stimulation, but is absent in supernatants from Con A-induced Th1 clones. CSIF can inhibit the production of IL-2, IL-3, lymphotoxin (LT)/TNF, IFN-gamma, and granulocyte-macrophage CSF (GM-CSF) by Th1 cells responding to antigen and APC, but Th2 cytokine synthesis is not significantly affected. Transforming growth factor beta (TGF-beta) also inhibits IFN-gamma production, although less effectively than CSIF, whereas IL-2 and IL-4 partially antagonize the activity of CSIF. CSIF inhibition of cytokine synthesis is not complete, since early cytokine synthesis (before 8 h) is not significantly affected, whereas later synthesis is strongly inhibited. In the presence of CSIF, IFN-gamma mRNA levels are reduced slightly at 8, and strongly at 12 h after stimulation. Inhibition of cytokine expression by CSIF is not due to a general reduction in Th1 cell viability, since actin mRNA levels were not reduced, and proliferation of antigen-stimulated cells in response to IL-2, was unaffected. Biochemical characterization, mAbs, and recombinant or purified cytokines showed that CSIF is distinct from IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IFN-gamma, GM-CSF, TGF-beta, TNF, LT, and P40. The potential role of CSIF in crossregulation of Th1 and Th2 responses is discussed.
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PMID:Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. 253 Nov 94

In the previous report, we investigated the effects of tissue culture on the APC function of murine epidermal Langerhans cells (LC) in the induction of allo-CTL in vitro, and found that (1) cultured ear LC expressed increased amounts of Ia antigens on their cell surface, and (2) they induced extremely enhanced levels of CTL over those produced by freshly prepared ear LC and also (3) cultured tail LC were proved to be able to induce CTL for the first time. It seemed that tissue culture decreased the functional heterogeneity among the murine ear LC and tail LC in addition to that among Ia+ APC in spleen and in epidermis. In this study, we investigated the culture conditions that increase the APC function of LC. Our data indicate that LC cultured with dermal components exhibited more enhanced APC function than LC cultured in single cell suspension with only epidermal cells. Recent studies indicate that IL-1 and GM-CSF, which keratinocytes release, are essential for freshly prepared LC to mature into highly efficient APC that resemble splenic dendritic cells. We found dermal factors are more important than epidermal ones for LC to mature in tissue culture.
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PMID:[The functional maturation of Langerhans cells in CTL induction during tissue culture]. 260 68

In the introduction, we asked how MHC molecules on the surfaces of APC make contact with antigen-specific receptors on the surfaces of T cells. We have reviewed two models in which antigen-specific contacts occur with primary leukocyte populations in vitro. One system involves resting T cells; the other sensitized T lymphoblasts. At the onset of a primary immune response, dendritic cells seem critical for binding and activating both CD4+ and CD8+ subsets. Given the current evidence, we suggest that dendritic cells literally find the right T cell clone, and not vice versa, and that dendritic cells do so by first binding and surveying T cells by an antigen-independent mechanism. In the efferent limb of immunity, other types of APC including B cells and macrophages bind and stimulate freshly sensitized T lymphoblasts. Freshly isolated epidermal Langerhans cells do not cluster T cells by an antigen-independent mechanism but acquire this capacity during epidermal suspension culture. Under the control of GM-CSF, the Langerhans cell becomes a powerful accessory cell for the primary or sensitization limb of T-dependent immune responses like the MLR and primary antibody response. Isolated lymphoid dendritic cells have many features in common with interdigitating cells in lymphoid T areas, and may be related to some of the irregularly-shaped Ia+ cells in certain epithelia and interstitial regions. Contact with dendritic cells may be important in both central and peripheral pathways of T cell sensitization in situ.
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PMID:The binding of antigen presenting cells to T lymphocytes. 307 54

Regulation of immune responses depends on interactions between APCs and T cells. Such cellular interactions are mediated by surface molecules including MHC class II Ags (DR) and CD28 ligands B7-1 (CD80) and B7-2 (CD86). Recent evidence indicates that the presence or absence of costimulatory molecules on APCs significantly influences the qualitative and quantitative nature of an immune response. In this report, we analyze two relevant cytokines in skin immunobiology, granulocyte-macrophage (GM)-CSF and IL-10, and demonstrate their effects on cultured dendritic cells obtained from dermis (DDCs) of normal skin and psoriatic lesions. For comparison, the effects on these professional APCs were contrasted with cultured blood-derived monocytes. Normal and psoriatic skin-derived DDCs express high levels of CD86 over CD80, and the overall hierarchy is DR > CD86 > CD80, whereas cultured monocytes express low and equivalent levels of CD80 and CD86. If Ab is added to GM-CSF at the initial period of cultivation, DDCs that emigrate have lower levels of CD86 without any detectable effect on CD80 or DR expression and display a reduced capacity to stimulate either superantigen-driven or alloantigen-responsive T cells. Conversely, by adding GM-CSF to monocytes, CD86 levels are enhanced. When IL-10 was added at the beginning of culture, DDCs had significantly lower levels of CD86, without any effect on CD80 or DR expression, and like anti-GM-CSF-treated cells, these DDCs had approximately a 50% reduction in their T cell-stimulating capacity. In contrast, when monocytes were treated identically with exogenously added IL-10, they retained their relatively low levels of CD80 and CD86 with no detectable change in APC function. Blocking studies of DDC:T cell interaction indicated that CD86 was more important than CD80. Thus, differential expression patterns and functional cytokine responses involving these APC populations may be relevant to skin disorders such as psoriasis, in which discordant patterns of CD28 ligand expression and disordered cytokine networks are present.
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PMID:Psoriatic skin-derived dendritic cell function is inhibited by exogenous IL-10. Differential modulation of B7-1 (CD80) and B7-2 (CD86) expression. 753 80

Injection of low doses of particulate hepatitis B surface Ag (HBsAg) into H-2d mice without adjuvants primes an Ld-restricted, S28-39-specific T cell response. This study indicates that dendritic cells (DC) and macrophages (M phi) both serve as APCs that support priming of CD8+ CTL precursors in vivo to exogenous HBsAg particles. After transfer into a syngeneic, naive host, HBsAg particle-pulsed DC, either freshly purified from skin or derived from a cloned DC line, efficiently primed class I-restricted, HBsAg-specific CTL precursors. M phi, either harvested from the peritoneal cavity or generated in macrophage-CSF-stimulated bone marrow cell cultures in vitro or derived from established, cloned M phi lines (PU5-1.8, J774A.1), pulsed with HBsAg particles in vivo or in vitro, elicited a class I-restricted, HBsAg-specific CTL response after adoptive transfer into naive hosts. The class I-restricted CTL response induced by HBsAg particle immunization was suppressed in carrageenan-treated mice, but was restored when carrageenan-treated mice were immunized with syngeneic, HBsAg-pulsed M phi. Selective elimination of M phi by liposome-incorporated dichloromethylene-diphosphonat did not suppress the induction of a CTL response of H-2d mice by HBsAg particle immunization. HBsAg-pulsed, freshly prepared DC are more potent than pulsed M phi in priming class I-restricted CTL in vivo. The relative importance of both types of APC in priming CTL remains to be resolved.
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PMID:Exogenous hepatitis B surface antigen particles processed by dendritic cells or macrophages prime murine MHC class I-restricted cytotoxic T lymphocytes in vivo. 756 Oct 24

A variety of studies suggest that the increased susceptibility of neonates to allergic and infectious respiratory diseases is due to delayed postnatal maturation of local mucosal immune function. We have recently demonstrated that the postnatal development of the major resident APC population in the respiratory tract (RT), class II MHC (Ia)-bearing dendritic cells (DC), is delayed relative to that in other tissues, and that both the intensity of Ia expression on these RTDC and their density within respiratory epithelia remain low until after weaning. The present study focuses on the functional capacity of neonatal RTDC and their responses to exogenous stimuli, and demonstrates that 1) infant Ia+ RTDC respond poorly to GM-CSF, under conditions that stimulate high levels of Ia expression and concomitant APC activity in adult cells; 2) both infant and adult RTDC contain a subpopulation of Ia- cells recognized by mAb OX62 that also respond poorly to GM-CSF; 3) inhalation of microbial stimuli or parenteral administration of IFN-gamma triggers rapid recruitment of DC into the airway epithelium and lung parenchyma of adults; this response is markedly attenuated in newborns and does not attain levels of competence until after weaning; and 4) endogenous macrophage-mediated suppression of the RTDC response to GM-CSF, the principal mechanism limiting in situ DC functional maturation in the adult lung, is highly active in the neonates. Taken together with earlier evidence of the relatively rapid postnatal development of T and B cell function in these animals, the present findings suggest that the sluggish performance of respiratory mucosal immune function(s) during infancy is attributable primarily to delayed maturation of local DC populations.
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PMID:Defective regional immunity in the respiratory tract of neonates is attributable to hyporesponsiveness of local dendritic cells to activation signals. 756 Oct 47

The induction of anergy in T cells is believed to be the result of triggering of the TCR in the absence of adequate costimulation mediated through the interaction of CD28 and its ligands, CD80 and CD86. Here, we demonstrate that stimulation of human group I allergen in Dermatophagoides pteronyssinus extract (Der p 1)-specific CD4+ Th2-like T cell clones with Der p 1-derived peptides in the absence of professional APC results in a state of nonresponsiveness. The induction of anergy occurred despite the expression of high levels of CD28, CD80, and CD86 on the surface of the T cell clones and was not prevented by the addition of anti-CD28 mAb. The anergic, Der p 1-specific, Th2 cells failed to mobilize calcium from intracellular stores, to proliferate, and to produce IL-2, IL-4, IL-13, GM-CSF, and TNF-alpha following optimal stimulation with Der p 1-derived peptide and autologous APC. However, they mobilized intracellular calcium following stimulation with Ca(2+)-ionophore and produced all of the above cytokines, including IFN-gamma, when stimulated with phorbol ester and Ca2+ ionophore. These results indicate that the anergic T cell clones are capable of responding to signals circumventing the TCR/CD3 complex activation pathway. In contrast to T cell clones optimally activated with peptide and APC, anergic T cells failed to induce IgG4 and IgE synthesis when cocultured with B cells, even in the presence of exogenous IL-4 or IL-13. Anergic T cells expressed normal levels of CD40L, suggesting that their inability to help in Ig production by B cells is due to conditions other than a lack of expression of this molecule. Finally, exogenous IL-2 restored the helper function of anergic Th2 T cells for IgE production by B cells, which was greatly enhanced by the addition of IL-4 or IL-13. These data suggest that induction of anergy in allergen-specific Th2 T cells by allergen-derived peptides may play an important role in the successful desensitization of allergic patients.
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PMID:Peptide-induced anergy in allergen-specific human Th2 cells results in lack of cytokine production and B cell help for IgE synthesis. Reversal by IL-2, not by IL-4 or IL-13. 759 75

1. There are several endogenous ligands that bind to I-receptors of both the I1 and I2 subclass. These include: (a) classic CDS, a partially purified entity isolated by the criteria that it displaces binding ligands to alpha 2- and I-receptors; (b) immunoreactive (ir)-CDS, a moiety that binds to antibodies raised against clonidine, para-amino-clonidine, or idazoxan; and (c) agmatine. 2. Classic-CDS, not yet defined structurally, binds to I1, I2, and alpha 2-adrenergic receptors, is neither a peptide nor a catecholamine, and has purportedly a molecular weight of 588 Da. By ligand binding assays, it was found in brain, serum, CSF, and placenta and in a neural-glial cell line. Partially purified classic CDS is bioactive. Like clonidine, it contracts aorta and vas deferens and inhibits platelet aggregation, effects largely attributable to agonism at alpha 2-adrenergic receptors. Unlike clonidine, it contracts rat gastric fundus and releases catecholamines from chromaffin cells, effects attributable to actions at I-receptors. Injected into the RVL, classic CDS alters arterial pressure, but the direction of change of pressure has differed between groups of investigators. However, in the absence of structure, it is possible that ligand binding and bioactivity may be attributable to different molecules. 3. Ir-CDS, also of unknown structure, is a material(s) that binds to antibodies raised against clonidine, PAC, or idazoxan. Ir-CDS, measured by radioimmunoassay, is unevenly distributed in brain with highest concentrations in the hypothalamus, midbrain, and dorsal medulla. It is contained in the gastric fundus, adrenal gland, heart, kidney, and serum in amounts substantially higher than found in brain. Ir-CDS may be elevated in the serum of some patients with hypertension and in the CSF of patients with structural brain disease. The concentration of ir-CDS and bioactivity on gastric fundus directly correlates, suggesting that it may share similarities with classic-CDS. However, until the structure of classic and ir-CDS is determined, the possibility that ligand binding and antibody recognition are properties of different molecules must be considered. 4. Agmatine (decarboxylated arginine) is the only endogenous molecule that, like CDS, binds to alpha 2- and I-receptors of both classes. It and its biosynthetic enzyme arginine decarboxylase are present in brain, and agmatine is widely distributed throughout the body. However, the distribution of agmatine and ir-CDS differs, whereas the biological actions of agmatine do not mimic those of classic CDS. Its presence raises the possibility of an alternative pathway for polyamine biosynthesis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Endogenous ligands of imidazoline receptors: classic and immunoreactive clonidine-displacing substance and agmatine. 767 40

The direct effects of IL-10 on the proliferation and lymphokine production of human peripheral blood T cells and CD4+ T cell clones representing the Th0, Th1-like, and Th2-like Th cell subsets were investigated in the absence of professional APC. IL-10 partially inhibited the proliferative responses of CD4+ human T cell clones induced by anti-CD2 or anti-CD3 mAb cross-linked on CD32 (Fc gamma RII)-transfected mouse L cells. Transfection of ICAM-1 or LFA-3 in CD32+ L cells resulted in enhanced proliferative responses of CD4+ T cell clones after activation by anti-CD3 mAb, whereas transfection of B7 in CD32+ L cells enhanced proliferative responses of CD4+ T cell clones after activation by anti-CD2 mAb. In addition, B7 expression on CD32+ L cells was required for activation of small resting T cells by anti-CD3 or anti-CD2 mAb. IL-10 inhibited the proliferation of T cell clones induced by anti-CD2 or anti-CD3 mAb on CD32+ L cells expressing these accessory molecules, indicating that interactions of LFA-3, ICAM-1, and B7 with their ligands on T cells did not overcome the inhibitory effects of IL-10. Inhibition of proliferation of T cell clones by IL-10 was in all instances completely neutralized by relatively low concentrations of IL-2, whereas IL-4 was ineffective. IL-10 did not affect the expression of the TCR/CD3 complex, CD2, LFA-1, CD28, or IL-2R alpha- or beta-chains, nor did it inhibit the induction of the latter two molecules on T cells after activation. Inhibition of proliferation was found to be the result of specific inhibition of IL-2 production by the responding T cell subsets, which occurred at the mRNA level. The production and mRNA levels of IL-4, IL-5, IFN-gamma, and granulocyte/macrophage-CSF were not affected by IL-10. Taken together, these results indicate that IL-10/IL-10R interaction on CD4+ T cell clones and peripheral blood T cells results in signaling pathways that specifically interfere with activation processes leading to IL-2 production. These direct inhibitory effects on IL-2 production by activated T cells may contribute to the general immunosuppressive activities of IL-10.
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PMID:Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. 768 12


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