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)

We have developed a panel of rat mAbs against dibutyryl cAMP-activated 5C2 cells. In this panel, one mAb, 1G10, recognized murine B7. Another mAb designated 2D10 did not bind to murine B7 but could recognize a surface molecule expressed only on dibutyryl cAMP-activated 5C2 mouse B lymphoma cells or on LPS-stimulated splenic B cells. This new molecule is referred to as early T cell costimulatory molecule-1 (ETC-1). From both activated 5C2 cells and splenic B cells, mAb 2D10 immunoprecipitated a 59- to 60-kDa protein, which was different from the 47- to 55-kDa murine B7 protein precipitated from the same cell populations. FACS analysis showed that, in contrast to B7, the expression of ETC-1 on 5C2 cells was induced by lower concentrations of dibutyryl cAMP and displayed a faster kinetics. LPS-stimulated splenic B cells expressed relatively low levels of B7 and much higher levels of ETC-1. Importantly, in an Ag presentation assay using activated 5C2 cells as APC, the secretion of IL-2 by C8A3 T hybrids was partially inhibited by mAb 2D10 alone and completely blocked by combination use of mAbs 2D10 and 1G10 in a dose-dependent and synergistic fashion. In a one-way primary MLR, mAb 2D10 alone at 0.1 to 1 microgram/ml inhibited T cell proliferation by 19 to 56%. However, an additive blocking effect (up to 76%) was observed when two mAbs were added in combination. Thus, our data have demonstrated that a novel T cell costimulatory molecule is present on activated murine B cells, which, in cooperation with B7, may play a critical role in optimal T cell activation.
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PMID:Monoclonal antibody 2D10 recognizes a novel T cell costimulatory molecule on activated murine B lymphocytes. 751 Jul 38

T cell lines (TCL) and CD4+ T cell clones (TCC) with specificity for the rye grass allergen Lolium perenne (Lol p) I were isolated from the blood of nine donors, six having active atopic disease, two being in remission, and one having IgE anti-Lol pI Abs but not atopic disease. The T cell epitopes of Lol pI were determined by TCLs and TCCs reactivity with 23 overlapping, 20 amino acid-long peptides spanning the entire length of the 230 amino acid-long allergen. In addition, the Th subsets (Th1, Th2, Th0, Thp) were determined by measuring IL-2, IFN-gamma, and IL-4 in the supernatants of TCC activated with Lol pI and irradiated APC. TCC from individuals from which a large panel of clones were obtained from 10(5) PBMC initial cultures recognized multiple peptides (5-9) and 23 overlapping peptides a total of 16 were recognized by at least one TCC from one of the patients. These 16 peptides were derived from all areas of the Lol pI molecule, indicating the ability of human Th cells to recognize many peptide epitopes on Lol pI. Although no clear cut immunodominant peptides were detected, T cell clones of 50% of the patients reacted with peptide 191-210. There was no correlation between peptide epitope reactivity and lymphokine secretion pattern of the TCC. Of 12 TCC obtained from six patients with active atopic disease, four (33%) were of Th1, five (42%) of Th2, one (8%) of Thp, and two (17%) of Th0 type. Of 14 TCCs isolated from three atopic donors in remission, five (36%) were of Th1, three (21%) of Th2, four (29%) of Thp, and two (14%) of Th0 type. The data demonstrate that T cells from rye grass pollen allergic patients can recognize multiple peptide epitopes on Lol pI scattered over the entire molecule. No correlation existed between epitope reactivity and lymphokine secretion pattern of the TCC.
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PMID:Recognition of T cell epitopes and lymphokine secretion by rye grass allergen Lolium perenne I-specific human T cell clones. 751 3

The interaction between lymphocytes and the resident hepatic macrophage, the Kupffer cell (KC), is relevant to the phenomenon of immune tolerance to Ags entering the liver. Tolerance to Ag administered via the portal vein can be prevented by the rare earth lanthanide metal, gadolinium (Gd). Therefore, we studied the ability of OVA-responsive, H-2d-restricted Th1 clones to proliferate in response to KCs from DBA/2J (H-2d) mice that had been injected with either saline (control) or a Gd solution. Whereas control KCs functioned as effective APCs, KCs from Gd-injected mice (GdKC) were incapable of sustaining the proliferative response of the Th1 clone to the 16 mer of OVA (323-339). This lack of proliferation was determined not to be caused by impaired Ag processing, but rather was the result of IFN-gamma-stimulated nitric oxide (NO) release by the APC: 1) In vitro addition of the nitric oxide synthase (NOS) inhibitor NG-methyl-L-arginine (NMMA) restored the ability of the Gd-treated KC to stimulate clone proliferation. 2) Additional of anti-IFN-gamma, but not anti-IL-2 or anti-IL-4, prevented the induction of NOS in the Gd-exposed KC and was associated with clone proliferation. 3) IFN-gamma levels from clone-GdKC-OVA cocultures closely paralleled the nitrite released by GdKCs. 4) Only the addition of rIFN-gamma, and not IL-2 or IL-4, to cultures of purified GdKCs resulted in the release of nitrite. The results of the study suggest an autocrine loop initiated by the interaction of the clone's TCR with the class II MHC molecule presenting processed OVA on the surface of KC. This interaction stimulates the Th1 lymphocyte to release IFN-gamma, which in turn induces NO release by KCs isolated from Gd-injected mice. This release of NO blocks Th1 proliferation. Such a feedback loop may have particular relevance to Ag-specific tolerance, which is not only induced by the administration of Ag into the portal vein, but is also prevented by Gd pretreatment of the recipient animal.
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PMID:Outcome of Kupffer cell antigen presentation to a cloned murine Th1 lymphocyte depends on the inducibility of nitric oxide synthase by IFN-gamma. 752 42

Signals initiated through both the TCR complex and CD28 are required for optimal activation of T lymphocytes. Recently, it has been demonstrated that CD28 interacts with two different ligands, designated CD80 (B7/B7-1) and CD86 (B70/B7-2). We have produced stable transfectants that express CD80, CD86, or both ligands and have examined their ability to costimulate T cell proliferation, cytokine production, and the generation of CTL. When we used small, resting human peripheral blood T cells as responders, both CD80 and CD86 transfectants efficiently costimulated anti-CD3 mAb-induced proliferation and the secretion of IL-2 and IFN-gamma. Additionally, both CD80 and CD86 transfectants were able to generate functional CTL. The magnitude and kinetics of these responses were similar, which indicates that both ligands provide efficient costimulatory signals. Because many APCs coexpress both CD80 and CD86, we compared the ability of anti-CD80 and anti-CD86 mAbs to inhibit allogeneic MLR stimulated with B lymphoblastoid cell lines and showed that it is necessary to inhibit interactions with both ligands to optimally block CD28-dependent proliferation. Given the limited homology of CD80 and CD86, it was surprising that the binding of CD28-Ig fusion protein to CD80 and that to CD86 transfectants were essentially indistinguishable. Binding of CTLA-4-Ig fusion protein to both transfectants also was quite similar, but was of higher affinity than CD28-Ig binding. Results from these studies indicate that both CD80 and CD86 are potent and similar costimulators of T lymphocytes. Therefore, the role of CD80 and CD86 in an immune response may be determined primarily by their differential expression on APC.
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PMID:CD80 (B7) and CD86 (B70) provide similar costimulatory signals for T cell proliferation, cytokine production, and generation of CTL. 752 24

Development of T cells during primary responses was investigated using pigeon cytochrome C-specific naive Th from TCR transgenic mice. Naive CD4 cells did not activate and help resting B cells. This failure was found to be primarily because the resting B cells were incapable of stimulating the naive Th. Provision of a costimulatory signal such as anti-CD28, or addition of APCs that express costimulatory molecules, such as dendritic cells, activated B cells, and B7+ and B7+ICAM(+)-expressing fibroblasts, induced naive Th activation and promoted T cell-dependent help for IgM secretion. T cell activation for as little as 24 h promoted helper activity, and Ig secretion required production of small amounts of IL-4 by the activated naive Th. On initial stimulation, naive Th secrete only IL-2. By mRNA analysis, activated naive Th were also shown to produce IL-4, however induction of IL-4 message only occurred 24 h after initial activation and required additional stimulation with Ag. A single exposure of naive CD4 to Ag/APC followed by 4 to 12 days in culture led to generation of effector Th which secreted IL-2 and some IFN-gamma, and no detectable IL-4 or IL-5, and which could only help B cells to IgM secretion. In contrast, similar cultures that received Ag/APC one or more times during this period generated effector cells capable of secreting easily detectable titers of IL-4 and IL-5, as well as IL-2 and IFN-gamma, and able to now promote IgG1 and IgE responses. Generation of these Th0-like effectors was accompanied by increasing amounts of IL-4 secreted during the culture period after each restimulation, and addition of anti-IL-4 in culture inhibited development of the capacity to produce Th2 cytokines. These studies reinforce the notion that naive CD4 must interact with a costimulatory professional APC, rather than a resting B cell, for initiation of the primary response, but show that such an interaction can result in rapid development of the ability to interact with and provide cognate help to B cells. They also suggest that if activated naive CD4 cells receive multiple stimulations from Ag/APC, enough endogenous IL-4 can be produced to drive differentiation into effectors secreting type 2 cytokines. The existence of such an autocrine feedback mechanism suggests that the amount and availability of Ag could influence the nature and polarization of the Th response.
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PMID:Recently activated naive CD4 T cells can help resting B cells, and can produce sufficient autocrine IL-4 to drive differentiation to secretion of T helper 2-type cytokines. 753 67

Male BXSB mice develop lupus-like disease and die early in life (4 to 5 mo) whereas female mice do not. Others have demonstrated that CD4+ cells from male mice support B cell resistance to tolerance induction to human gamma-globulin (HGG). In this study, male and female mice tolerized at 2 mo of age with deaggregated HGG and subsequently immunized with HGG in comparison with mice immunized only were tested for anti-HGG Ab responses. CD4+ cells from draining lymph nodes of these mice were tested in culture for proliferation and production of cytokine mRNA and protein in response to HGG plus APC. Tolerized male but not female mice produced anti-HGG Abs of both the IgG1 and IgG2a isotypes. HGG-stimulated CD4+ cells from immunized male and female mice that were not tolerized produced IL-2, IL-4, IL-5, IFN-gamma, and TNF-beta mRNA as well as IL-2 and IL-4 protein, whereas tolerized, immunized mice of both sexes failed to proliferate or produce either IL-2 or IL-4 or express any cytokine mRNA in response to HGG in vitro. A resistance in tolerance induction in male mice, as determined by anti-HGG Abs, was also observed at 3 mo of age. Although a resistance to tolerance was also seen in terms of proliferation in the 3-mo-old males, production of IL-2 or IL-4 protein was still not observed. Thus, all T cell subsets identified by cytokine expression profiles were tolerized not only from females but also from males, of which the latter appeared to show some resistance to tolerance induction.
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PMID:In vivo tolerance induction and associated cytokine production by subsets of murine CD4+ T cells. 753 93

Efficient initiation of a CD4 T cell response requires both activation through the TCR and costimulation provided by molecules on APC with counterreceptors on the T cell. We investigated the relative contribution of the ICAM-1:LFA-1 and B7:CD28/CTLA-4 costimulatory pathways in naive T cell activation, using either anti-CD28 Ab or fibroblast cell lines transfected with I-Ek, which express either no costimulatory molecules, ICAM-1 alone, B7-1 alone, or ICAM-1 and B7-1 together. Peptide Ag or immobilized anti-CD3 was used to provide the TCR signal. CD4 T cells from mice transgenic for the V beta 3/V alpha 11 TCR, which recognize a peptide of pigeon cytochrome c complexed to I-Ek, were used as a source of naive T cells. Naive T cells stimulated with Ag or anti-CD3 responded well to high numbers of APC expressing either ICAM-1 alone or B7-1 alone. However, APC expressing both ICAM-1 and B7-1 were much better stimulators of proliferation and IL-2 secretion at low cell numbers, and were far superior inducers of IL-2 at higher numbers, indicating a synergy between the two pathways. Stimulation provided by ICAM-1 could not be solely attributed to adhesive strengthening of other pathways, since costimulation was seen when immobilized anti-CD3 was used and when ICAM-1 only APC were added, indicating that ICAM-1 was in fact acting as a classic costimulatory molecule. Both the magnitude of the response and the amount of costimulation required for response were dependent on the intensity of TCR interaction. These results suggest that an efficient naive T cell response requires both a strong TCR signal and more than one costimulatory signal that will synergize with the TCR signal. This offers an explanation as to why APC such as dendritic cells and activated B cells, which express high levels of multiple costimulatory/adhesion molecules, are the only APC that elicit naive T cell responses.
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PMID:Costimulatory requirements of naive CD4+ T cells. ICAM-1 or B7-1 can costimulate naive CD4 T cell activation but both are required for optimum response. 754 26

Self-thyroid epithelial cell (TEC)-reactive CD8+ and CD4+ T cell lines were established by culturing T cells that infiltrate in autoimmune thyroiditis lesions. We investigated the properties of CD8+ T cell lines and clones in comparison with previously characterized CD4+ T cell lines/clones. Although the recognition of self-Ag by anti-TEC CD4+ T cell lines/clones required the cooperation of syngeneic spleen cells as APC, a representative CD8+ line (N4C) was stimulated with syngeneic TEC in the absence of APC. Precise analysis of MHC restriction using N4C-derived clones revealed that CD8+ clones recognize self-Ag on TEC in the context of class I MHC molecules. Most CD8+ clones were also found to express TCR with V beta specificities that were different from those observed for anti-TEC CD4+ clones. N4C cells produced IL-2, IFN-gamma, and TNF-alpha beta, but not IL-4 and IL-5 after stimulation with TEC, thus exhibiting the profile of lymphokine production similar to that expressed by CD4+ Th1 on one hand, but on the other, they showed the functional property that has not been observed for anti-TEC CD4+ clones. Namely, they elicited appreciable levels of cytolytic effects on syngeneic TEC in a short-term (4-h) 51Cr release assay. Thus, these results indicate that self-TEC-reactive CD8+ T cell lines/clones recognize Ag directly on TEC in a class I MHC-restricted way so as to exhibit various functions including the Th1-like profile of lymphokine production and anti-TEC cytolysis. The results are also discussed in terms of the nature of self-Ag presented with class I MHC molecules on TEC, as well as the potential roles of anti-TEC CD8+ T cells in the pathogenesis of thyroiditis.
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PMID:Self-thyroid epithelial cell (TEC)-reactive CD8+ T cell lines/clones derived from autoimmune thyroiditis lesions. They recognize self-thyroid antigens directly on TEC to exhibit T helper cell 1-type lymphokine production and cytotoxicity against TEC. 754 27

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

IL-12 influences cytokine synthesis in unprimed CD4+ T cells by enhancing IFN-gamma synthesis and enhancing the development of Th1 cells, but its effects upon Ag-primed T cells, which are thought to have relatively fixed cytokine profiles, is less clear. We investigated the capacity of IL-12 to modify cytokine synthesis in allergen-specific human CD4+ T lymphocytes from allergic donors after in vitro stimulation. CD4+ T cells were obtained from the peripheral blood of subjects with allergic rhinitis, depleted of activated T cells, and cultured with APCs and allergen. IL-12 dramatically inhibited the development of IL-4 and IL-10 synthesis, while it enhanced T cell secretion of IFN-gamma and IL-2, and enhanced Ag-specific T cell proliferation. The inhibitory effect of IL-12 on IL-4 synthesis was not dependent on the presence of IFN-gamma, was greatest when IL-12 was added at the initiation of culture, and was minimal when added late, indicating that resting memory CD4+ T cells were more sensitive than activated CD4+ T cells to the effects of IL-12. The effect of IL-12 on IL-4 and IL-10 synthesis was not dependent on the APC type, because IL-12 decreased IL-4 synthesis when either B cells or monocytes served as APCs. These results indicate that IL-12 may be therapeutically beneficial in the treatment of allergic diseases in which allergen-specific T cells characteristically produce enhanced quantities of IL-4 and IL-10.
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PMID:IL-12 inhibits the production of IL-4 and IL-10 in allergen-specific human CD4+ T lymphocytes. 760 91


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