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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2A3 monoclonal antibody (gamma 1, kappa) is a novel high-affinity reagent for detecting the human interleukin 2 (IL-2) receptor. The antibody inhibits IL-2 binding to its receptor and is an antagonist of IL-2 action. Detailed analysis of the mechanism of binding of the IgG, (Fab')2 and Fab' of 2A3 antibody shows that the bivalent species cross-link on the cell surface when bound. Measurements of IL-2 receptor expression on digitonin-permeabilized cells suggest that the intracellular pool of receptors is small. The antibody will bind to IL-2 receptors on glutaraldehyde-fixed cells in the presence of Triton X-100. This property is used in designing an assay for quantitative measurements of IL-2 receptor concn in solution. This assay can be used to monitor receptor protein during purification to homogeneity.
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PMID:Quantitative measurement of human interleukin 2 receptor levels with intact and detergent-solubilized human T-cells. 393 Sep 53

Inflammatory bowel disease (IBD) may be an immunologically mediated disorder in which T cells are unable to respond appropriately to cell surface-associated antigens. To test this possibility, 37 patients with IBD, 24 with Crohn's disease and 13 with ulcerative colitis who were not being treated with immunosuppressive therapy were studied. The ability of T cells to proliferate in response to autologous or allogeneic cells, i.e., the autologous or allogeneic mixed-lymphocyte reaction (MLR) was tested. The autologous MLR was depressed using patient cells compared to control cells, regardless of disease type or activity (1564 +/- 223 cpm versus 3300 +/- 381 cpm, P less than 0.05) while the allogeneic MLR was depressed in patients with active disease only (29,833 +/- 2871 cpm versus 46,799 +/- 3340 cpm, P less than 0.01). The ability of T cells to recognize and lyse allogeneic cells, allogeneic cell-mediated lympholysis (CML), was also low in patients with active disease (24 +/- 4% versus 37 +/- 3%, P less than 0.05). Since T-cell proliferation and cytotoxicity depend upon adequate production of and response to a T-cell growth factor, interleukin 2 (IL-2), IL-2 production and responsiveness in IBD were studied. IL-2 production by patient T cells in response to phytohemagglutinin was only 39% of control values, P less than 0.05. The response to IL-2 was measured by the increase in T-cell proliferation in the autologous MLR in medium alone or medium supplemented with IL-2. Control T-cell proliferation rose from 3300 +/- 381 cpm to 10,761 +/- 428 cpm with exogenous IL-2 (P less than 0.001). Patient T-cell proliferation rose from 1564 +/- 223 cpm to 6817 +/- 771 cpm with IL-2 (P less than 0.001) but did not reach the level of the IL-2-supplemented control autologous MLR (P less than 0.05). In addition, the percentage of activated patient T cells having Tac antigen (IL-2 receptor) was depressed (P less than 0.05). These findings did not vary with disease type or activity. It is concluded from these data that peripheral blood T lymphocytes from patients with IBD have a diminished response to cell surface antigens which is associated with a decrease in IL-2 production and receptor generation. These defects may be responsible for the depressed T-cell proliferation and cytotoxicity that accompany IBD.
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PMID:T-cell abnormalities in inflammatory bowel disease are mediated by interleukin 2. 623 13

Transferrin is required by many cells for growth. Mitogen-induced T lymphocyte proliferation is dependent on the presence of both interleukin 2 (IL-2; T-cell growth factor) and transferrin, even though resting lymphocytes do not have receptors for either. Exposure to mitogen (phytohemagglutinin) alone is sufficient to induce transient appearance of IL-2 receptors on lymphocytes. Using monoclonal antibodies to the IL-2 receptor and to the transferrin receptor, we examined those signals required for transferrin receptor induction during T lymphocyte proliferation. Our study has revealed that (i) monocytes, or a monocyte substitute such as the phorbol ester tetradecanoylphorbol 13-acetate, are required for transferrin receptor expression after mitogen exposure; (ii) the presence of IL-2 receptors is necessary for transferrin receptor induction; (iii) antibody to the IL-2 receptor inhibits thymidine incorporation (DNA synthesis) in lymphocytes, but only if administered before transferrin receptors have appeared; and (iv) antitransferrin receptor antibody inhibits DNA synthesis but has minimal effect on IL-2 receptor expression. Thus, IL-2 receptor induction leads to transferrin receptor induction and subsequent initiation of DNA synthesis. These data indicate that IL-2 stimulates T lymphocyte proliferation, at least in part, by induction of transferrin receptors on these cells.
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PMID:Transferrin receptor induction in mitogen-stimulated human T lymphocytes is required for DNA synthesis and cell division and is regulated by interleukin 2. 630 12

Human interleukin-2 (IL-2) is a glycoprotein of relative molecular mass (Mr) 15,000, which is released by T lymphocytes on stimulation with antigen or mitogen and functions as a T-cell growth factor (TCGF) by inducing proliferation of activated T cells. It is generally accepted that resting or activated B cells do not respond directly to IL-2 but require for their proliferation other T-cell-derived lymphokines usually referred to as B-cell growth factors (BCGFs). Recently, however, a monoclonal antibody reacting with the IL-2 receptor molecules expressed by activated T cells (anti-Tac) was shown to react also with certain B tumour cells; in addition, murine B cells proliferate in response to pure human IL-2. We now show that recombinant IL-2, derived from Escherichia coli expressing the human gene, is able to promote strong proliferation of human B cells activated with protein-A-rich Staphylococcus aureus Cowans strain I. Moreover, we demonstrate that the anti-Tac antibody also reacts with S. aureus-activated normal B cells and inhibits sharply the proliferative response of such cells to IL-2. Finally, immunoprecipitation experiments reveal that anti-Tac defines similar molecules on activated T and B cells.
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PMID:Human interleukin-2 promotes proliferation of activated B cells via surface receptors similar to those of activated T cells. 643 35

Dendritic epidermal T cells (DETC) are skin-specific members of the epithelial gamma delta T-cell family in mice. We have reported previously that the growth of DETC is promoted by interleukin (IL)-2 in an autocrine fashion, or by IL-7, which is secreted by neighboring keratinocytes. Here we report that DETC growth is promoted by IL-15, a newly discovered T-cell growth factor that is produced in lymphoid as well as nonlymphoid tissues. Recombinant IL-15 promoted the growth of the 7-17 DETC line in a time- and dose-dependent fashion. Using monoclonal antibodies against alpha-, beta-, or gamma c-chains of the IL-2 receptor complex, we observed that the combination of anti-beta chain and anti-gamma c chain antibodies blocked IL-15 responsiveness completely, whereas anti-alpha chain had no effect. These results indicate that this gamma delta T-cell line uses the beta/gamma c heterodimer for proliferative responses to IL-15. Antibodies against IL-2 or IL-7 did not block IL-15-driven proliferation of 7-17 DETC, indicating that IL-15 promotes their growth in an IL-2- and IL-7-independent manner. Both the surface expression of beta/gamma c heterodimers and the IL-15 responsiveness of 7-17 DETC were highest 1 to 8 days after concanavalin A stimulation, and both declined substantially 21 days after stimulation, illustrating regulation by the state of cell activation. Working with epidermal cells that were freshly procured from CBA mice, we noted that IL-15 promoted conavalin-A-triggered growth of Thy-1+ cells (i.e., DETC), but not of the Thy-1- cells. The gamma c-chain was not expressed by freshly procured DETC, becoming detectable within 48 h after concanavalin A stimulation. We propose that IL-15 facilitates the growth of epithelial gamma delta T cells by a beta/gamma c receptor-dependent mechanism.
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PMID:Interleukin (IL)-15 promotes the growth of murine epidermal gamma delta T cells by a mechanism involving the beta- and gamma c-chains of the IL-2 receptor. 749 Apr 80

Stimulation via the T-cell growth factor interleukin 2 (IL-2) leads to tyrosine phosphorylation of Shc, the interaction of Shc with Grb2, and the Ras GTP/GDP exchange factor, mSOS. Shc also coprecipitates with the IL-2 receptor (IL-2R), and therefore, may link IL-2R to Ras activation. We have further characterized the Shc-IL-2R interaction and have made the following observations. (i) Among the two phosphotyrosine-interaction domains present in Shc, the phosphotyrosine-binding (PTB) domain, rather than its SH2 domain, interacts with the tyrosine-phosphorylated IL-2R beta chain. Moreover, the Shc-PTB domain binds a phosphopeptide derived from the IL-2R beta chain (corresponding to residues surrounding Y338, SCFTNQGpYFF) with high affinity. (ii) In vivo, mutant IL-2R beta chains lacking the acidic region of IL-2Rbeta (which contains Y338) fail to phosphorylate Shc. Furthermore, when wild type or mutant Shc proteins that lack the PTB domain were expressed in the IL-2-dependent CTLL-20 cell line, an intact Shc-PTB domain was required for Shc phosphorylation by the IL-2R, which provides further support for a Shc-PTB-IL-2R interaction in vivo. (iii) PTB and SH2 domains of Shc associate with different proteins in IL-2- and T-cell-receptor-stimulated lysates, suggesting that Shc, through the concurrent use of its two different phosphotyrosine-binding domains, could assemble multiple protein complexes. Taken together, our in vivo and in vitro observations suggest that the PTB domain of Shc interacts with Y338 of the IL-2R and provide evidence for a functional role for the Shc-PTB domain in IL-2 signaling.
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PMID:Evidence for a role for the phosphotyrosine-binding domain of Shc in interleukin 2 signaling. 864 66

Interleukin-2 (IL-2), the cytokine also known as T-cell growth factor, has multiple immunoregulatory functions and biological properties not only related to T-cells. In the past decade, substantial evidence accumulated to suggest that IL-2 is also a modulator of neural and neuroendocrine functions. First, extremely potent effects of IL-2 on neural cells were discovered, including activities related to cell growth and survival, transmitter and hormone release and the modulation of bioelectric activities. IL-2 may be involved in the regulation of sleep and arousal, memory function, locomotion and the modulation of the neuroendocrine axis. Second, the concept that IL-2 could act as a neuroregulatory cytokine has been supported by reports on the presence in rodent and human brain tissues of IL-2-like bioactivity, IL-2-like immunoreactivity, IL-2-like mRNA, IL-2 binding sites, IL-2 receptor (IL-2R alpha) and beta chain mRNA and IL-2R immunoreactivity. IL-2 and/or IL-2R molecules mainly localize to the frontal cortex, septum, striatum, hippocampal formation, hypothalamus, locus coeruleus, cerebellum, the pituitary and fiber tracts, such as the corpus callosum, where they are likely expressed by both neuronal and glial cells. Although the molecular biology of the brain IL-2/IL-2R system (including its relation to IL-15/IL-15R alpha) is not yet fully established by cloning and complete sequencing of all respective components, similarities (and to some extent differences) to peripheral counterparts are now apparent. The ability of IL-2 to readily penetrate the blood-brain barrier further suggests that this cytokine could regulate interactions between peripheral tissues and the central nervous system. Taken together, these data suggest that IL-2 of either immune and CNS origin can have access to functional IL-2R molecules on neurons and glia under normal conditions. Additionally, dysregulation of the IL-2/IL-2 receptor system could lead or contribute to functional and pathological alterations in the brain as in the immune system. Understanding the neurobiology of the IL-2/IL-2 receptor system should also help to explain neurologic, neuropsychiatric and neuroendocrine side effects occurring during IL-2 treatment of peripheral and brain tumors. Immunopharmacological manipulation either aiming at the activation or suppression of IL-2 signaling should consider functional interference with constitutive and inducible IL-2 receptors on brain cells in order to fulfil the high expectations associated with the use of this cytokine as a promising agent in immunotherapies, especially of brain tumors.
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PMID:Interleukin-2 as a neuroregulatory cytokine. 880 16

A homogeneous receptor-ligand assay based on fluorescence resonance energy transfer is described. In the assay, recombinant human interleukin 2 (IL-2) and a monoclonal antibody against the human IL-2 receptor alpha chain were labelled with a highly fluorescent europium chelate and Cy5, respectively. As a result of a successful receptor-ligand complex formation, these labels are brought into close proximity, which will thereby allow an energy transfer to occur from the donor (europium) to the acceptor (Cy5), upon excitation of the donor. Utilization of specific non-neutralizing antibodies made it possible to use crude hIL-2R alpha membranes prepared from recombinant baculovirus-infected Sf9 insect cells. The specific energy transfer was measured at the emission wavelength of Cy5 using a time-resolved fluorometer. The data presented, demonstrate that this assay design can be utilized for saturation as well as competitive binding experiments in addition to regular receptor titrations. As a rapid simple homogeneous assay it is particularily suitable for high throughput screening analyses.
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PMID:Homogeneous time-resolved IL-2-IL-2R alpha assay using fluorescence resonance energy transfer. 970 12

Studies of the biology of the IL-2 receptor have played a major part in establishing several of the fundamental principles that govern our current understanding of immunology. Chief among these is the contribution made by lymphokines to regulation of the interactions among vast numbers of lymphocytes, comprising a number of functionally distinct lineages. These soluble mediators likely act locally, within the context of the microanatomic organization of the primary and secondary lymphoid organs, where, in combination with signals generated by direct membrane-membrane interactions, a wide spectrum of cell fate decisions is influenced. The properties of IL-2 as a T-cell growth factor spawned the view that IL-2 worked in vivo to promote clonal T-cell expansion during immune responses. Over time, this singular view has suffered from increasing appreciation that the biologic effects of IL-2R signals are much more complex than simply mediating T-cell growth: depending on the set of conditions, IL-2R signals may also promote cell survival, effector function, and apoptosis. These sometimes contradictory effects underscore the fact that a diversity of intracellular signaling pathways are potentially activated by IL-2R. Furthermore, cell fate decisions are based on the integration of multiple signals received by a lymphocyte from the environment; IL-2R signals can thus be regarded as one input to this integration process. In part because IL-2 was first identified as a T-cell growth factor, the major focus of investigation in IL-R2 signaling has been on the mechanism of mitogenic effects in cultured cell lines. Three critical events have been identified in the generation of the IL-2R signal for cell cycle progression, including heterodimerization of the cytoplasmic domains of the IL-2R beta and gamma(c) chains, activation of the tyrosine kinase Jak3, and phosphorylation of tyrosine residues on the IL-2R beta chain. These proximal events led to the creation of an activated receptor complex, to which various cytoplasmic signaling molecules are recruited and become substrates for regulatory enzymes (especially tyrosine kinases) that are associated with the receptor. One intriguing outcome of the IL-2R signaling studies performed in cell lines is the apparent functional redundancy of the A and H regions of IL-2R beta, and their corresponding downstream pathways, with respect to the proliferative response. Why should the receptor complex induce cell proliferation through more than one mechanism or pathway? One possibility is that this redundancy is an unusual property of cultured cell lines and that primary lymphocytes require signals from both the A and the H regions of IL-2R beta for optimal proliferative responses in vivo. An alternative possibility is that the A and H regions of IL-2R beta are only redundant with respect to proliferation and that each region plays a unique and essential role in regulating other aspects of lymphocyte physiology. As examples, the A or H region could prove to be important for regulating the sensitivity of lymphocytes to AICD or for promoting the development of NK cells. These issues may be resolved by reconstituting IL-2R beta-/-mice with A-and H-deleted forms of the receptor chain and analyzing the effect on lymphocyte development and function in vivo. In addition to the redundant nature of the A and H regions, there remains a large number of biochemical activities mediated by the IL-2R for which no clear physiological role has been identified. Therefore, the circumstances are ripe for discovering new connections between molecular signaling events activated by the IL-2R and the regulation of immune physiology. Translating biochemical studies of Il-2R function into an understanding of how these signals regulate the immune system has been facilitated by the identification of natural mutations in IL-2R components in humans with immunodeficiency and by the generation of mice with targeted mutations in these gen
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PMID:Biology of the interleukin-2 receptor. 975 37

The fusion protein toxin DAB389IL-2 is composed of the catalytic and transmembrane domains of diphtheria toxin genetically linked to human interleukin 2 (IL-2). This fusion toxin is selectively toxic for eukaryotic cells which express the high-affinity form of the IL-2 receptor and the mechanism of intoxication parallels that of native diphtheria toxin. We used site-directed mutagenesis to introduce Pro residues into each of the three helical layers of the transmembrane domain. Although each of the mutations results in the complete loss of cytotoxic activity, individual mutants were found to vary with respect to channel formation in planar lipid bilayers, binding affinity and melting temperature. We propose that each of the three helix layers plays a critical role in the productive delivery of the catalytic domain to the cell cytosol.
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PMID:The effects of helix breaking mutations in the diphtheria toxin transmembrane domain helix layers of the fusion toxin DAB389IL-2. 979 31


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