UNIPROT:P14784 - FACTA Search

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

The IL-2 receptor beta-chain (IL-2R beta), a specificity-determining subunit in the IL-2R complex with a restricted tissue distribution pattern, is essential for signal transduction. Our previous studies demonstrate that the continuous treatment of mice with anti-IL-2R beta resulted in the complete disappearance of NK cells and Thy-1+ dendritic epidermal cells (Thy-1+ dEC), suggesting that signals through IL-2R beta are critically involved in development of these lymphocyte subsets. However, these lymphocyte subsets are reported to be apparently unaffected in the IL-2-deficient mice. To further examine the biological roles of the IL-2R beta, transgenic mice carrying the IL-2R beta transgene were generated. In these mice, high levels of the cell surface expression of the IL-2R beta were observed in essentially all hematopoietic lineage cells, and CD4+ T cells as well as CD8+ T cells showed vigorous cell proliferation upon IL-2 stimulation. Surprisingly, NK cells marked with a high expression of NK1.1 in the spleen and Thy-1+ dEC in the skin were completely absent in transgenic mice. However, the development of other lymphocyte subsets including conventional alpha beta TCR+ cells, gamma delta TCR+ cells and B cells remained apparently intact. From these observations together with previous data on IL-2-deficient mice, we speculate that factors, other than IL-2 that utilizes the IL-2R beta as its functional receptor subunit, may have a vital role in the development of NK cells and Thy-1+ dEC. Implications for possible in vivo functions of over-expressed IL-2R beta are discussed.
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PMID:Dysregulated expression of the IL-2 receptor beta-chain abrogates development of NK cells and Thy-1+ dendritic epidermal cells in transgenic mice. 749 52

The interleukin 2 receptor beta chain (IL-2R beta) is preferentially expressed in natural killer (NK) cells, but is not detected in a majority of resting T and B cells. We recently established a novel monoclonal antibody (mAb) to murine IL-2R beta and examined in vivo the effect of the mAb in mice. We found that intraperitoneal injection of the anti-IL-2R beta mAb into adult mice resulted in a selective in vivo elimination of splenic NK function in various mouse strains. The reduction of NK cell function is associated with complete disappearance of NK1.1+ cells in C57BL/6 mice. Other lymphocyte subsets in the thymus and spleen were uncompromised. T cell function was not affected by the mAb treatment as judged by allogeneic cytotoxic T cell induction. The single injection of anti-IL-2R beta mAb caused a long-term elimination of splenic NK cells, lasting for at least 5 wk. We also found that NK and/or NK precursor cells become susceptible to the mAb treatment only after birth, suggesting that functional maturation of NK cells in terms of IL-2R beta expression is a later event in the course of NK cell development. The use of the anti-IL-2R beta mAb will be useful in defining the physiological role of NK cells in host defense as well as dissecting their developmental pathway in vivo.
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PMID:Selective long-term elimination of natural killer cells in vivo by an anti-interleukin 2 receptor beta chain monoclonal antibody in mice. 835 49

Guanine ribonucleosides that have been substituted at the C8 position with bromine or thiol groups have been shown previously to activate NK cells and to act as sparing agents for IL-2 in the generation of LAK cells. Herein, we examined a disubstituted guanosine, 7-allyl-8-oxoguanosine (loxoribine), for the ability to activate NK cells and to interact with IL-2 in the generation of LAK cells. Loxoribine enhanced the NK activity of murine spleen cells with optimal activity occurring after 10 h of culture at concentrations ranging from 50 to 150 microM. The response was, however, short lived, approaching baseline levels by 24 h of culture. In contrast, if spleen cells were cultured with a suboptimal concentration of IL-2 (10 U/ml) in combination with loxoribine, a prolonged and enhanced cytolytic activity was seen. The enhancement was greatest if the loxoribine and IL-2 were both added to the cultures at the beginning of the incubation period. Analysis of the expression of the alpha-chain of the IL-2 receptor after loxoribine stimulation indicated that gene transcription was enhanced within 4 h, and cell surface expression was observed on NK1.1+ Thy1+ and NK1.1+ Thy1- cell populations within 24 h of loxoribine treatment. The priming of LAK cell precursors by loxoribine did not appear to be mediated by IFN-alpha/beta, because anti-IFN antibodies did not block either the activation of cytolytic cells by IL-2 or the expression of IL-2 receptors after culture with loxoribine. These data suggest that one mechanism by which cytolytic precursor cells are primed by loxoribine to respond to IL-2 faster and with enhanced cytolytic activity may be through the expression of high affinity IL-2 receptors due to the up-regulation of the alpha-chain.
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PMID:Loxoribine (7-allyl-8-oxoguanosine) activates natural killer cells and primes cytolytic precursor cells for activation by IL-2. 837 66

Murine liver contains alpha beta T cells with intermediate TCR (TCRint) as well as alpha beta T cells with bright TCR. Liver TCRint cells express NK1.1 Ag (NK1+ TCRint) and IL-2 receptor beta chain, both of which are NK cell markers and are not expressed on conventional T cells. Liver NK1+ TCRint cells consist of CD4-8- double negative T cells and CD4+ T cells and have V beta 8+ T cell preponderance. They are dependent on class Ib or CD1 molecules of APC for their development. They can also develop thymus independent manner, because athymic nude mice have this population. These NK1+ TCRint cells in the livers of both euthymic and athymic mice were found to be activated by systemic administration of IL-12 and increased NK1 expression (NK1high TCRint) and cytotoxicity against various NK-sensitive and resistant tumors. Cytotoxicity assays after treatment of IL-12 stimulated hepatic MNC with respective Abs and C revealed that CD4+ NK1high TCRint cells are responsible for IL-12 induced cytotoxicity. Although NK1+ TCRint cells were normally few in the lungs, a significant proportion of NK1high TCRint cells with strong cytotoxicity was also induced in the lung by IL-12. Interestingly, adoptive transfer of IL-12 stimulated hepatic MNC into other mice, which were pre-injected with tumors, inhibits hepatic metastases of EL4 cells and pulmonary metastases of 3LL cells as similarly as IL-12 administration. Transfer experiments after treatment of IL-12 stimulated hepatic MNC with respective Ab and C revealed that depletion of either NK1+ cells, CD3+ cells or CD4+ cells but not CD8+ cells greatly impaired antimetastatic effect in both organs. Thus, CD4+ NK1high TCRint cells are a major antimetastatic population, especially, against hematogenous metastases.
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PMID:[The function and role of extrathymic T cells]. 853 54

Interleukin-2 (IL-2) plays a pivotal role in the cellular and humoral immune responses directed against foreign antigens. We characterized the in vitro and in vivo properties of a chimeric protein consisting of mouse IL-2 fused to the mouse IgG2b Fc domains. This fusion protein binds to IL-2 and Fc receptors and supports IL-2-dependent cell proliferation but does not mediate lysis of IL-2 receptor-positive cells in the presence of murine complement in vitro. However, in vivo the IL2-IgG2b fusion protein suppresses both cellular and humoral immune responses after immunization with sheep erythrocytes. Surprisingly, delayed hypersensitivity is inhibited despite a dramatic increase of splenic CD3+ and NK1.1+ lymphocytes, indicating that altered homing of IL2-IgG2b-activated lymphocytes rather than cytolysis prevents these cells from accumulating in areas of inflammation. Although in vitro the IL2-IgG2b fusion protein does not alter proliferation of B cells in response to mitogenic stimulation, IgM production in response to sheep erythrocytes is profoundly inhibited in mice treated with the IL2-IgG2b fusion protein. Since no side effects are observed, the IL2-IgG2b fusion protein may expand the therapeutic repertoire of reagents used for the treatment of allograft rejection and autoimmune diseases.
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PMID:Suppression of cell-mediated and humoral immune responses by an interleukin-2-immunoglobulin fusion protein in mice. 863 31

To analyze the early development of T cell precursors in the absence of TCR gene rearrangement, recombinase-activating gene-deficient (RAG-2 -/-) thymocytes were compared with thymocytes from SCID mice on the C.B-17 (BALB) and B6 genetic backgrounds. RAG-2 -/- thymocytes accumulate as quiescent cells with a heat-stable Ag (HSA)-positive CD25+ CD44- c-kit(low) phenotype, resembling normal cells just before selection for functional TCR beta-chain expression. CD44 and c-kit progressively down-regulate in the HSA+ subset, providing a background-independent and TCR-independent developmental clock. On this basis, compared with RAG-2 -/- thymocytes, SCID thymocytes 1) arrest at more heterogeneous, and generally earlier, stages; 2) accumulate to lower overall cell numbers; and 3) maintain higher populations of cycling and activated G1 cells, showing both increased responsiveness and increased cell death. B6-SCID thymocytes appear to die particularly early. Low levels of Fas were observed on "advanced" HSA+ SCID thymocytes but not on any RAG-2 -/- thymocytes, suggesting a potential difference in activation state or mechanism of death. In both RAG-2 -/- and SCID thymocytes, there are also two discrete subsets of HSA(low) CD25- CD44+ c-kit+ cells: a Sca-1+ CD44++ CD122- NK1.1- putative progenitor subset and an NK-like Sca-1- CD44+(+) CD122+ NK1.1+ subset. The absolute cell numbers in these HSA(low) subsets and the extent of NK cell differentiation, measured by perforin expression, are nearly constant in all the mutant strains analyzed, in contrast to the HSA+ CD25+ population, which was expanded in the RAG-2 -/-. Thus, the SCID thymocytes appear to undergo a normal generation but a premature death as compared with the RAG-2 -/- thymocytes.
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PMID:Different developmental arrest points in RAG-2 -/- and SCID thymocytes on two genetic backgrounds: developmental choices and cell death mechanisms before TCR gene rearrangement. 912 63

An unusual subset of mature T cells expresses natural killer (NK) cell-related surface markers such as interleukin-2 receptor beta (IL-2R beta; CD122) and the polymorphic antigen NK1.1. These "NK-like" T cells are distinguished by their highly skewed V alpha and V beta repertoire and by their ability to rapidly produce large amounts of IL-4 upon T cell receptor (TCR) engagement. The inbred mouse strain SJL (which expresses NK1.1 on its NK cells) has recently been reported to lack NK1.1+ T cells and consequently to be deficient in IL-4 production upon TCR stimulation. We show here, however, that SJL mice have normal numbers of IL-2R beta+ T cells with a skewed V beta repertoire characteristic of "NK-like" T cells. Furthermore lack of NK1.1 expression on IL-2R beta+ T cells in SJL mice was found by backcross analysis to be controlled by a single recessive gene closely linked to the NKR-P1 complex on chromosome 6 (which encodes the NK1.1 antigen). Analysis of a panel of inbred mouse strains further demonstrated that lack of NK1.1 expression on IL-2R beta+ T cells segregated with NKR-P1 genotype (as assessed by restriction fragment length polymorphism) and thus was not restricted to the SJL strain. In contrast, defective TCR induced IL-4 production (which appeared to be a unique property of SJL mice) seems to be controlled by two recessive genes unlinked to NKR-P1. Collectively, our data indicate that "NK-like" T cells develop normally in SJL mice despite genetically distinct defects in NK1.1 expression and inducible IL-4 production.
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PMID:Natural killer-like T cells develop in SJL mice despite genetically distinct defects in NK1.1 expression and in inducible interleukin-4 production. 913 Jun 46

Mercury induces a systemic autoimmune condition characterized by auto-antibodies to the nucleolar protein fibrillarin (AFA) and systemic immune-complex (IC) deposits in genetically susceptible mouse strains. This study examines T cell activation and cytokine production following mercury exposure in genetically susceptible and resistant strains. Mercury injected s.c., according to the protocol for induction of autoimmunity, caused an early T cell activation, measured as an increase of IL-2-producing cells, and increased expression of the IL-2-receptor proteins CD25 and CD122 and of the proliferation marker CD71 on days 2-4 in the susceptible A.SW and A. TH strains. This was followed by a long-lasting increase in the number of T cells, dominated by CD4(+) cells. Mice of the susceptible A.SW strain showed a modest increase of TNF-alpha-, IFN-gamma-, and IL-4-producing cells after 4-6 days, and a very distinct increase of IL-4-producing cells on days 8-10. The susceptible SJL strain (H-2(s)), severely deficient in Th2-promoting CD4(+), NK1.1(+) T cells, showed no increase of IL-4(+) cells on days 8-10. Instead, the number of IFN-gamma-producing cells was increased. Susceptible mice developed an increase of Ig-producing cells, AFA, and systemic IC-deposits. Genetically mercury-resistant A.TL mice showed a minimal increase of T cells, but no increase in cytokine-producing cells. We conclude that autoimmunogenic doses of HgCl2 induce an activation and proliferation of T cells in genetically susceptible mouse strains, as well as a broad increase of cytokine-producing cells, followed by a late predominance of the Th2-associated IL-4. One strain, severely deficient in Th2-promoting CD4(+), NK1.1(+) T cells, lacked the increase in IL-4(+) cells, indicating that a predominantly Th2-response is not necessary for induction of autoimmunity by mercury. However, a Th2-dominated response led to a faster and stronger B cell activation.
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PMID:Effects of the murine genotype on T cell activation and cytokine production in murine mercury-induced autoimmunity. 923 98

The administration of low dose interleukin-2 (IL-2) results in a selective expansion of natural killer (NK) cells in vivo, and promotes the differentiation of NK cells from hematopoietic precursor cells in vitro. We have previously shown that stem cell factor (SCF ), the ligand to the c-kit tyrosine kinase receptor, enhances IL-2-induced NK cell proliferation and differentiation in vitro. Here, we investigated the effects of SCF plus IL-2 delivered to mice in vivo. Eight-week-old C57BL/6 mice were treated with a continuous subcutaneous infusion of IL-2 (1 x 10(4) IU/d) plus a daily intraperitoneal dose of SCF (100 microg/kg/d), IL-2 alone, SCF alone, or vehicle alone for 8 weeks. The in vivo serum concentration of IL-2 ranged between 352 +/- 12.0 pg/mL and 606 +/- 9.0 pg/mL, achieving selective saturation of the high affinity IL-2 receptor, while the peak SCF serum concentration was 296 +/- 13.09 ng/mL. Alone, the daily administration of SCF had no effect on the expansion of NK cells. The continuous infusion of IL-2 alone did result in a significant expansion of NK1.1+CD3- cells compared to mice treated with placebo or SCF. However, mice treated with both SCF and IL-2 showed an increase in the absolute number of NK cells that was more than twofold that seen with IL-2 alone, in the spleen (P </= .005), bone marrow (P </= .025), and blood (P < .05). NK cytotoxic activity against YAC-1 target cells was significantly higher for mice treated with SCF plus IL-2, compared to mice treated with IL-2 alone (P </= .0005). Interferon-gamma (IFN-gamma) production in cytokine-activated splenocytes was also greater for the SCF plus IL-2 group, over IL-2 treatment alone (P </= .01). The effect of SCF plus IL-2 on NK cell expansion was likely mediated via NK cell precursors, rather than mature NK cells. In summary, we provide the first evidence that SCF can significantly enhance expansion of functional NK cells induced by the prolonged administration of low dose IL-2 in vivo. Since the NK cell is a cytotoxic innate immune effector and a potent source of IFN-gamma, this therapeutic strategy for NK cell expansion may serve to further enhance innate immune surveillance against malignant transformation and infection in the setting of cancer and/or immunodeficiency.
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PMID:Stem cell factor enhances interleukin-2-mediated expansion of murine natural killer cells in vivo. 934 49

We have developed a stroma-free culture system in which mouse marrow or thymus cells, known to be enriched for lymphoid progenitors, can be driven to generate natural killer (NK) cells. Culture of lineage marker (Lin)-, c-kit+, Sca2+, interleukin (IL)-2/15Rbeta (CD122)- marrow cells in IL-6, IL-7, stem cell factor (SCF), and flt3 ligand (flt3-L) for 5-6 d followed by IL-15 alone for an additional 4-5 d expanded the starting population 30-40-fold and gave rise to a virtually pure population of NK1.1+, CD3- cells. Preculture in IL-6, IL-7, SCF, and flt3-L was necessary for inducing IL-15 responsiveness in the progenitors because the cells failed to significantly expand when cultured in IL-15 alone from the outset. Although culture of the sorted progenitors in IL-6, IL-7, SCF, and flt3-L for the entire 9-11-d culture period caused significant expansion, no lytic NK1.1+ cells were generated if IL-15 was not added, demonstrating a critical role for IL-15 in NK differentiation. Thus, two distinct populations of NK progenitors, IL-15 unresponsive and IL-15 responsive, have been defined. Similar results were obtained with Lin-, CD44+, CD25-, c-kit+ lymphoid progenitors obtained from adult thymus. The NK cells generated by this protocol lysed the NK-sensitive target YAC-1 and expressed markers of mature NK cells with the notable absence of Ly-49 major histocompatibility complex (MHC) receptors. However, despite the apparent lack of these inhibitory MHC receptors, the NK cells generated could distinguish MHC class I+ from class I- syngeneic targets, suggesting the existence of novel class I receptors.
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PMID:Generation of lytic natural killer 1.1+, Ly-49- cells from multipotential murine bone marrow progenitors in a stroma-free culture: definition of cytokine requirements and developmental intermediates. 934 20

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