Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epithelial cells of the intestine seem to act as antigen-presenting cells to surrounding lymphoid tissue and may be crucial to maintain the pool of peripheral T lymphocytes. The scope of this study was to carry out an immunophenotypic and ultramicroscopic analysis of purified human enterocytes to elucidate their role as antigen-presenting cells, in the immune responses in the gut-associated lymphoid tissue. A method has been developed to obtain purified and viable human enterocyte populations, later labeled with relevant monoclonal antibodies directed to leukocyte antigens and subjected to cytofluorometric analysis. Phenotypic analysis revealed the presence of markers common to "classical" antigen-presenting cells (CD14, CD35, CD39, CD43, CD63 and CD64), reinforcing the idea that enterocytes may act as such. Moreover, several integrins (CD11b, CD11c, CD18, CD41a, CD61 and CD29) were also found. CD25 (IL-2 receptor alpha chain) and CD28, characteristic of T cells, were detected on the surface of these cells; this latter finding rises the possibility that enterocytes could be activated by IL-2 and/or via CD28 through binding to its ligands CD80 or CD86. Finally, the presence of CD21, CD32, CD35 and CD64 that may bind immune complexes via Fc or C3, suggests their participation in the metabolism of immune complexes. Furthermore, the finding of a Birbeck's-like granule in the cytoplasm of the cells, shows that enterocytes contain an ultramicroscopic feature previously thought to be characteristic of Langerhans' cells, an antigen-presenting cell. The phenotype detected on the surface of enterocytes, along with their ultramicroscopic characteristics, suggests that they may play an important role in the immune responses elicited in the gut, presenting antigens to surrounding lymphoid cells, and establishing cognate interactions with them.
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PMID:Cell surface phenotype and ultramicroscopic analysis of purified human enterocytes: a possible antigen-presenting cell in the intestine. 945 11

Ceramide generated by lysosomal acid sphingomyelinase (aSMase) has been proposed to contribute to CD28 co-stimulatory signaling pathways. We used an aSMase-deficient mouse line (asmase-/-) to elucidate the role of the aSMase in splenocytes stimulated with either a combination of anti-CD3 and anti-CD28 antibodies, the lectin concanavalin A (Con A) or the superantigen staphylococcal enterotoxin B. All stimuli were shown to induce IL-2 expression, Con A additionally triggered the expression of high-affinity IL-2 receptor. However, in asmase-/- mice secretion of IL-2 was significantly reduced, whereas the intracellular IL-2 levels were elevated. Proliferation of anti-CD3/anti-CD28 or Con A-stimulated aSMase-deficient splenocytes was reduced up to 50% after 72 h in comparison to wild-type cells. We conclude that ceramide generated by aSMase is not involved in CD28 signal transduction, but rather a perturbation of the secretory system is responsible for the impaired proliferation of aSMase-deficient splenocytes.
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PMID:Ceramide-independent CD28 and TCR signaling but reduced IL-2 secretion in T cells of acid sphingomyelinase-deficient mice. 954 82

In rheumatoid arthritis (RA), T cells in the inflamed joint are considered to play a crucial role in the pathogenesis. However, despite the fact that synovial T cells have an activated memory phenotype, they are functionally suppressed upon combined CD3 and CD28 stimulation. Here, we analyzed the contribution of both CD3 and CD28 to the hyporesponsiveness of synovial T cells in RA. In contrast to the low CD3 responsiveness of synovial fluid (SF) T cells compared to peripheral blood (PB) T cells, the CD28 co-stimulatory response was observed to be unaffected. Hyporesponsiveness of SF T cells has previously been associated with decreased levels of intracellular glutathione (GSH), an antioxidant and regulator of the intracellular redox state. Treatment of SF T cells with N-acetylcysteine, an antioxidant and replenisher of GSH, selectively improved CD3-induced responses, while leaving CD28 responsiveness unaffected. These data show that the CD3 pathway is highly sensitive to intracellular GSH alterations, whereas CD28 responsiveness is relatively refractory. Furthermore, in support for a functional role of CD28 co-stimulation, it was demonstrated that CD28 ligation acted in synergy with the IL-2 receptor gamma chain signaling cytokine IL-15 in the enhancement of the ex vivo survival of SF T cells. These data indicate that CD28 co-stimulatory capacity of SF T cells, in contrast to CD3 stimulation, remains intact despite an altered intracellular redox state. Thereby, CD28 stimulation may contribute to the persistence of T cells at the site of inflammation, which might be of relevance in the pathogenesis of RA.
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PMID:CD28 co-stimulation is intact and contributes to prolonged ex vivo survival of hyporesponsive synovial fluid T cells in rheumatoid arthritis. 960 60

The actions of a humanised therapeutic CD4 mAb YHB.46 on T cell activation were investigated in vitro. Soluble YHB.46 IgG or YHB.46-derived F(ab')2 fragments caused inhibitions of up to 100% of the proliferation of purified CD4+ T cells activated with immobilised CD3 mAb. The inhibitory effects of the CD4 mAb were equally potent in both CD45RA+ and CD45RO+ T cell subset proliferation assays. Inhibitory effects on DNA synthesis were nto explicable by increased T cell apoptosis. YHB.46 was inhibitory even when added 70 h after exposure of cells to immobilised CD3 mAb, but it had little effect on IL-2 receptor-driven proliferation signals. The CD4 mAb inhibited the CD3-induced expression of the CD25 and CD69 activation markers on the T cell surface and suppressed CD40 ligand expression, but not that of CD25 and CD69, when their expression was induced by phorbol ester plus ionomycin. YHB.46 also exerted a profound inhibitory effect on the production of IL-2, IL-4, and IL-10, irrespective of whether T cells were activated with CD3 mAb or with phorbol ester plus ionomycin. The inhibitory effects of YHB.46 on CD4+ T cell proliferation were partially prevented by the addition of exogenous IL-2 or autologous monocytes and were completely prevented by activating T cells with a novel CD3-CD28 bivalent F(ab')2 reagent. However, the inhibitory effects of YHB.46 on T cell proliferation were equipotent in the presence or the absence of CTLA-4Ig, showing that the CD4 mAb was not acting on CD28-induced activation signals per se. Our results show that the inhibitory effects of YHB.46 on T cell activation do not involve CD28 or IL-2 receptor signalling, but are directed at the TCR-mediated G0-G1 transition. These findings in vitro predict that YHB.46 may act as a potent immunosuppressant in the clinical context.
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PMID:A humanised therapeutic CD4 mAb inhibits TCR-induced IL-2, IL-4, and IL-10 secretion and expression of CD25, CD40L, and CD69. 963 88

Lymphocyte activation gene (LAG)-3, a member of the Ig superfamily, has been characterized as an activation antigen of T cells and NK cells. LAG-3 has been proposed as an alternate ligand for HLA class II due to some sequence homology and similarities in exon-intron organization with CD4. Here, we report the functional evaluation of a soluble Ig fusion molecule of human LAG-3 (LAG-3-Ig) in T cell activation assays. Cytofluorimetry studies revealed LAG-3-Ig binding predominantly to class II-expressing cells. In functional assays, inhibition of primary allogeneic mixed lymphocyte response (MLR) and murine-human xenogeneic MLR was observed in the presence of LAG-3-Ig. Effects of LAG-3-Ig addition were not observed on mitogen-, recall antigen- or superantigen-mediated stimulation. Cytotoxic T lymphocyte effector functions were also not affected by LAG-3-Ig. Inhibition of alloresponses by LAG-3-Ig occurred within the first 24 h of activation, resulting in a strong inhibition of IL-2 production. Unlike blockade of the CD28 receptor, however, LAG-3-Ig-mediated inhibition could not be reversed by exogenous IL-2 supplementation. Cytofluorimetric analysis of the phenotype of cells exposed to LAG-3-Ig in MLR cultures revealed a decrease in IL-2 receptor expression (CD25) on CD4+ cells in all donors tested. Based on the results from these studies, we conclude that LAG-3-Ig inhibits alloresponses of naive peripheral blood lymphocytes, by blocking the activation of a subpopulation of allo reactive cells.
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PMID:Soluble human lymphocyte activation gene-3 modulates allospecific T cell responses. 964 16

The 90 kDa heat shock protein (Hsp90) is a molecular chaperone aiding the folding of nuclear hormone receptors and protein kinases. Hsp90-mediated folding can be disrupted by the Hsp90-specific drug, geldanamycin. Here we provide evidence for the inhibition of the CD28-specific BW 828 antibody-mediated activation of human T lymphocyte proliferation, IL-2 secretion and IL-2 receptor expression by geldanamycin. Our results suggest that the major cytoplasmic chaperone, Hsp90, plays an important role in CD28-mediated T lymphocyte activation.
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PMID:The Hsp90-specific inhibitor, geldanamycin, blocks CD28-mediated activation of human T lymphocytes. 974 95

The consequences of T-cell receptor engagement (signal 1) are profoundly affected by the presence or absence of co-stimulation (signal 2). T-cell receptor (TCR) stimulation in the absence of CD28-mediated co-stimulation not only results in little interleukin (IL)-2 production, but induces a long lasting hyporesponsive state known as T-cell clonal anergy. The addition of CD28 ligation to signal 1, on the other hand, results in the production of copious amounts of IL-2. Our laboratory has utilized CD4+ Th 1 clones in an effort to understand the molecular events resulting in enhanced IL-2 production by co-stimulation and the inhibition of IL-2 production in anergy. Our current studies have focused on defining the post-transcriptional effects of CD28-enhanced IL-2 production. The data suggest that a major component of CD28's ability to regulate IL-2 production occurs at the level of message stability and involves the 3'-untranslated region of the message. In terms of anergy, our recent studies support the notion that it is not the result of TCR engagement in the absence of co-stimulation, but rather signal 1 in the absence of IL-2 receptor signaling and proliferation. Furthermore, T-cell anergy appears to be an active negative state in which IL-2 production is inhibited both at the level of signal transduction and by cis-dominant repression at the level of the IL-2 promoter.
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PMID:Molecular regulation of interleukin-2 expression by CD28 co-stimulation and anergy. 985 Aug 68

Discovery of novel biological and pharmaceutical agents directed against discrete molecular targets in the lympnocyte activation sequence has enabled the effective control of graft rejection by the use of combinatorial immunosuppressive therapy. Chimeric and humanized monoclonal antibodies against T-cell receptor CD3 complex chains or the IL-2 receptor block T-cell function without inducing activation, and do not cause the cytokine release syndrome of first generation products. Biological blockade of co-stimulatory molecules including CD40L and CD28 produces immunological allograft unresponsiveness in primates, though this effect is not yet proven in humans. Heterogeneity in clinical response to pharmaceutical agents is often explained by pharmacokinetic factors of absorption, metabolism and elimination. The use of microemulsion technology has increased the absorption and efficacy of cyclosporine in all organ transplants, so that there is little difference in efficacy between this agent and tacrolimus. Mycophenolate mofetil is not maximally effective alone, but significantly reduces the relative risk of acute rejection in combination with an immunophilin binding agent. It is also effective when introduced at the time of rejection. Whether it can replace other agents for maintenance immunosuppression is now under investigation. Sirolimus, the latest pharmaceutical agent to complete phase III trials, acts to inhibit IL-2 driven lymphocyte proliferation and reduces the risk of acute rejection to below 20%. Multiple pharmacokinetic interactions occur within and between these agents, so that pharmacokinetic monitoring is increasingly important. At present there are few tools to detect pharmacodynamic interactions, although reporter gene constructs and intracellular cytokine labeling offer exciting possibilities for biological monitoring. Despite these advances, none of these interventions confers demonstrable long-term benefit in graft survival or function. Acute rejection can not therefore be assumed to be a simple surrogate for chronic injury, and research must be re-focused to determine the relevant targets for long-term immunosuppression.
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PMID:New immunosuppressive strategies. 986 62

Immunologic effector cells termed cytokine-induced killer (CIK) cells are generated in vitro from peripheral blood lymphocytes by addition of interferon-gamma, interleukin (IL)-2, IL-1 and an antibody against CD3. CIK cells have been shown to eradicate established tumors in a SCID mouse/human lymphoma model. CIK cells are dependent on exogenous cytokines such as IL-2, IL-7, or IL-12. We studied the effect of these cytokines in detail. Cellular proliferation was analyzed using an MTT proliferation assay, surface antigen expression via flow cytometry, cytotoxic activity using an LDH release assay, and apoptosis via flow cytometric analysis. IL-2, IL-7 and IL-12 led to significant growth of lymphocytes. Cells grown in IL-2 and IL-7 showed higher proliferation rates than cells grown in IL-12 according to the MTT assay. Concerning surface antigen expression, exogenous IL-7 led to a decrease in IL-7 receptor expression (4.8% from 60.4%) and exogenous IL-2 to a decrease in IL-2 receptor expression (61.2% from 73.2%). CD28 expression was higher in cells grown in IL-7 (77.3%) than in cells grown in IL-2 (62.5%). IL-12 led to a decrease in ICAM-1 adhesion molecule expression (57.7% from 76.7%) and an increase in CD56 expression compared with exogenous IL-7. IL-7 led to higher number of CD4-positive cells than IL-2 (53.0% vs 49.5%). No significant difference was found between IL-2, IL-7 and IL-12 in cytotoxic activity measured in an LDH release assay. Small amounts of apoptotic cells were found with all cytokines. However, the percentage of necrotic cells was higher with exogenous IL-12 than with IL-2 or IL-7. In summary, CIK cells can be generated using exogenous IL-2, IL-7 or IL-12. No difference in cytotoxic activity was found. However, significant differences were found in cell proliferation rates, antigen expression and percentage of necrotic cells.
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PMID:Generation of cytokine-induced killer cells using exogenous interleukin-2, -7 or -12. 987 75

Human breast carcinoma tumor-infiltrating lymphocytes (TIL) express activation antigens in situ indicative of ongoing immune response-CD28, CD45RO, CD69, CD71, and DR. However, interleukin 2 (IL-2) receptor was poorly expressed: CD25 was detected in only 1/24 samples and CD122 in only 2/24 samples. Furthermore, isolated breast cancer TIL were defective in proliferative response but recover when treated with recombinant IL-2. Nineteen of 24 tumor samples expressed B7-1, B7-2, and CD28 protein, showing that absence of costimulator proteins or counter ligand was not the basis for TIL proliferative deficit. Expression of IL-2 activity was not detected; however, mRNA encoding IL-2 was produced and translatable in vitro. These findings show that human breast cancer tumor-induced repression of IL-2 RNA translation is the basis of failure of TIL to express the IL-2 receptor and subsequent T cell hyporesponsiveness.
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PMID:Repression of interleukin-2 mRNA translation in primary human breast carcinoma tumor-infiltrating lymphocytes. 987 15


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