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

We previously demonstrated the existence of a third component, p64, of IL-2 receptor (IL-2R), tentatively named the gamma chain of IL-2R. Our recent studies provided evidence suggesting that the gamma chain endows the beta chain of IL-2R with IL-2 binding ability. The gamma chain was detected in lymphoid transfectants of IL-2R beta cDNA, which showed the intermediate-affinity IL-2R, but not in nonlymphoid transfectants of IL-2R beta cDNA, which showed no IL-2 binding activity. The comparative study between two subclones of lymphoid MOLT4 transfectant of IL-2R beta cDNA demonstrated that the amount of the gamma chain coprecipitated with IL-2R beta was proportional to numbers of the IL-2 binding sites. These results suggest the possibility that the gamma chain associates with IL-2R beta and has an important role in formation of the intermediate-affinity IL-2R complex. On the other hand, we have also demonstrated the association of IL-2R beta with a certain tyrosine kinase, of which activation by IL-2 could be indispensable process at the initial pathway of signal transduction.
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PMID:The IL-2/IL-2 receptor system: involvement of a novel receptor subunit, gamma chain, in growth signal transduction. 130 8

Interleukin 2 (IL-2) receptors expressed on the surface of activated T cells and natural killer (NK) cells exhibit a variety of affinity states depending on their subunit composition. Low-affinity binding is associated with a 55-kDa alpha chain, intermediate-affinity binding with a 70-75-kD beta chain, and high-affinity binding with a bimolecular complex of the alpha and beta subunits. In a previous study of the IL-2 receptors expressed on NK cells obtained from cancer patients after in vivo IL-2 therapy, we documented a discrepancy between the level of beta chain and the level of intermediate-affinity IL-2 binding sites expressed on the cell surface. Based on this result, we postulated that formation of intermediate-affinity receptor sites required a component in addition to the beta chain, and that this component was present at limiting levels in the patient NK cells. In the present study we have examined the structure of the intermediate-affinity receptor complex using monoclonal antibodies that recognize the beta chain, but that do not interfere with its ability to bind IL-2. Evidence is presented establishing the physical association of a novel protein of 64 kD with the beta chain in intermediate-affinity IL-2 binding sites. This molecule, termed IL-2R gamma chain, coprecipitated with beta chains prepared from cells that had been incubated with IL-2, but was undetectable in immunoprecipitates prepared in the absence of IL-2. Examination of gamma chain expression in post-IL-2 therapy NK cells, where only low levels of intermediate-affinity IL-2 binding were detectable, revealed that the gamma chain was associated with, on average, only 10-12% of the beta chains expressed on such cells. This contrasted with approximately equal levels of beta and gamma chain expression on YT cells, a cell line that has both high levels of cell surface beta chain expression and high levels of IL-2 binding. Thus, the ratio of gamma chain to beta chain present in the immunoprecipitates roughly correlated with the proportion of beta chain involved in intermediate-affinity receptor sites. This result suggests that the 64-kD gamma chain is the component responsible for regulating the affinity of IL-2 association with the beta subunit. By further defining the structural components necessary for IL-2 receptor formation, these studies provide additional insight into mechanisms whereby lymphocytes might regulate their responsiveness to IL-2.
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PMID:Characterization of the interleukin 2 receptors (IL-2R) expressed on human natural killer cells activated in vivo by IL-2: association of the p64 IL-2R gamma chain with the IL-2R beta chain in functional intermediate-affinity IL-2R. 150 Aug 59

We previously established a monoclonal antibody, TU11 mAb, which is specific for human IL-2 receptor (IL-2R) beta chain (p75) and does not inhibit IL-2-binding to IL-2R beta. Using TU11 mAb, we first demonstrated the existence of a third component, p64, of IL-2R, tentatively named the gamma chain of IL-2R. TU11 mAb precipitated not only the beta chain but also the alpha and gamma chains in the lysates of cells bearing the high-affinity IL-2R in the presence of IL-2 without any chemical crosslinker. The gamma chain was also detected in lymphoid MOLT alpha beta and MOLT beta cells, which were stably transfected with both alpha and beta cDNA, and with beta cDNA alone, respectively, but not in fibroblastoid COS alpha beta and COS beta cells, which were stably transfected with both alpha and beta cDNA, and with beta cDNA alone, respectively. Furthermore, IL-2-mediated growth signals were transduced in the lymphoid transfectant cells but not in the fibroblastoid transfectant cells, suggesting the possibility that the gamma chain along with the beta chain has an essential role in the transduction of IL-2-mediated growth signals. Using TU11 mAb, we secondly demonstrated that IL-2 rapidly induces tyrosine phosphorylation of both the beta and gamma chains in an IL-2-dose-dependent manner. The tyrosine phosphorylation of beta and gamma chains were also detected in the lymphoid transfectant cells but not in the fibroblastoid transfectant cells, indicating the correlation between tyrosine kinase activation and IL-2-mediated growth signaling. The beta chain was phosphorylated in in vitro on serine, threonine and tyrosine residues, but the gamma chain was phosphorylated in in vitro predominantly on tyrosine residues, suggesting the possibility that the gamma chain itself is a tyrosine kinase molecule.
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PMID:IL-2-induced signal transduction: involvement of tyrosine kinase and IL-2 receptor gamma chain. 209 Aug 80

Interleukin-13 (IL-13) induced a potent mitogenic response in IL-3-dependent TF-1 cells and DNA synthesis to a lesser extent in MO7E and FDC-P1 cells. IL-13 stimulation of these lines, like IL-4 and insulin-like growth factor-1 (IGF-1), resulted in tyrosine phosphorylation of a 170-kD substrate. The tyrosine-phosphorylated 170-kD substrate strongly associated with the 85-kD subunit of phosphoinositol-3 (PI-3) kinase and with Grb-2. Anti-4PS serum readily detected the 170-kD substrate in lysates from both TF-1 and FDC-P1 cells stimulated with IL-13 or IL-4. These data provide evidence that IL-13 induces tyrosine phosphorylation of the 4PS substrate, providing an essential interface between the IL-13 receptor and signaling molecules containing SH2 domains. IL-13 and IL-4 stimulation of murine L cell fibroblasts, which endogenously express the IL-4 receptor (IL-4R alpha) and lack expression of the IL-2 receptor gamma subunit (IL-2R gamma), resulted in tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1)/4PS. Enhanced tyrosine phosphorylation of IRS-1/4PS was observed in response to IL-4, but not IL-13 treatment of L cells transfected with the IL-2R gamma chain. These results indicate that IL-13 does not use the IL-2R gamma subunit in its receptor complex and that expression of IL-2R gamma enhances, but is not absolutely required for mediating IL-4-induced tyrosine phosphorylation of IRS-1/4PS.
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PMID:The insulin receptor substrate-1-related 4PS substrate but not the interleukin-2R gamma chain is involved in interleukin-13-mediated signal transduction. 749 80

The recognition of the monocyte/macrophage-activating properties of IL-2 has broadened our image of the biological effects of this lymphokine from those of a T cell growth factor to those of a molecule with pleiotropic effects. The detailed analysis of the mechanisms of action of IL-2 including its biological effects on different cell types and the regulation of its receptors has increased dramatically the spectrum of the biological responses that can be modified by IL-2. The regulation of the expression of the IL-2 receptor subunits differs in terms of response to extracellular stimuli and intracellular control, suggesting that the response to IL-2 will vary depending on the nature and extent of environmental stimulation. Furthermore, the fact that the IL-2R gamma chain can be part of the receptor for IL-4, IL-7, and perhaps other cytokines indicates that IL-2 may modulate the response of monocytes simply by binding or releasing the IL-2R gamma chain and thus modulating the responsiveness to IL-4 or IL-7. Conversely, the extent of utilization of IL-2R gamma chain by various cytokines may dictate the monocytic response to IL-2. In fact, the availability of IL-2R gamma chain seems to be the limiting factor in the response of monocytes to IL-2. Modulation of cytokine receptors is an integral part of the control of the IL-2 response. The induction of CSF-1 receptor by IL-2 and the positive effect of CSF-1 on the duration of the cytotoxic response in IL-2-stimulated monocytes are an interesting example of a synergistic interaction of potential physiological relevance. The response of monocytes to IL-2 can also be modulated by inhibitory circuits, such as those involving TGF-beta 1, IFN-gamma, and IL-4. However, IFN-gamma and IL-4 can also activate monocytes and the timing and relative concentrations of the various cytokines may be critical variables in determining the ultimate monocyte phenotype. These studies have given us a glimpse of a very complex picture composed of multiple backgrounds and several players. However, the present information is not sufficient to make meaningful predictions of the resulting monocyte phenotype in an inflammatory reaction in which multiple cytokines are involved.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Interleukin-2 and human monocyte activation. 782 65

Human severe combined immunodeficiency (SCID) includes an X-linked SCID (XSCID) characterized by a complete absence of mature T cells, hypogammaglobulinemia and a normal or elevated number of B cells. XSCID results from mutation in the IL-2 receptor (IL-2R) gamma chain gene, which is thought to be involved in not only IL-2R but also IL-4R and IL-7R mediated signals. To investigate the VDJ recombination and Ig repertoire development in the absence of the IL-2R gamma chain, we intended to study the CDR3 junction in peripheral blood B cells of three XSCID patients. A total of 101 different CDR3 junctions were cloned following polymerase chain reaction amplification of polyclonal peripheral blood lymphocyte DNA. Sequence analysis of CDR3 junctions revealed that the primary antibody repertoire of the Ig H chain gene was assembled in a normal fashion. Among the JH segments, overexpression of JH3 segments was significant in XSCID patients compared with age-matched controls. D segment usage in XSCID was very similar to that in age-matched controls. All of the XSCID JH regions except for two clones were equal to germline JH genes, showing little or no evidence of somatic mutation. The results indicate that the immature JH segment is preferentially utilized and somatic mutation is absent in the CDR3 junction of the Ig H chain gene of XSCID patients.
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PMID:Preferential utilization of the immature JH segment and absence of somatic mutation in the CDR3 junction of the Ig H chain gene in three X-linked severe combined immunodeficiency patients. 786 64

IL-2 regulates growth and differentiation of various types of cells in the immune system via its interaction with IL-2 receptor (IL-2R). The high and intermediate-affinity IL-2Rs, which consist of the alpha beta gamma heterotrimer complex and the beta gamma heterodimer complex, respectively, harbor the function of the intracellular signal transduction, indicating that the beta and gamma chains are indispensable for the signal transduction but not the alpha chain. The reconstitution studies of IL-2Rs with alpha, beta and gamma chain genes demonstrated that each subunit has potential for altering the affinity of the receptor, and the cytoplasmic domains of the beta and gamma chains participate in signal transduction in terms of cell growth, activation of alpha tyrosine kinase and enhancement of c-myc, c-fos and c-jun transcription. The region containing the SH2 homologous sequence of the gamma chain should have a critical function for signal transduction. On the other hand, common subunits are known to be shared among receptors for IL-3, IL-5 and GM-CSF, and receptors for IL-6, LIF, OSM and LIF. We have demonstrated that the monoclonal antibody specific for the IL-2R gamma chain completely inhibited not only IL-2-dependent cell growth but also IL-4-dependent, IL-7-dependent, and IL-9-dependent cell growth, suggesting that the gamma chain is possibly shared among receptors for IL-2, IL-4, IL-7 and IL-9. Impairment of the gamma chain function is considered to be closely related to human XSCID characterized by profound T cell defect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Structure and function of IL-2 receptor subunits]. 802 15

X-linked severe combined immunodeficiency is characterized by severe and persistent infections from early life resulting from profound impairment of both cellular and humoral immune function. XSCID is characterized by an absence or diminished number of T cells and histologic evidence of hypoplastic and abnormal differention of the thymic epithelium. The discovery that this disease results from the mutations of the IL-2R gamma chain was surprising since IL-2-deficient mice and human SCID patients had milder phenotypes. This led to the speculation that IL-2R gamma would prove to be a common gamma chain, gamma c, which would play important roles in other cytokine receptors in addition to the IL-2 receptor. There is now compelling evidence to support a role in at least two other cytokine receptors, namely the IL-4 and IL-7 receptors. Thus, with inactivation of gamma c, multiple cytokine systems are simultaneously affected, resulting in the profoundly impaired phenotype of XSCID. It is possible and even likely that gamma c will be found to be a functional component of additional receptors as well. These findings have resulted in a significant improvement in our understanding of the pathophysiologic development of the defects in XSCID and also have important ramifications for prenatal and postnatal diagnosis, carrier female identification, and gene therapy for XSCID.
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PMID:The molecular basis of X-linked severe combined immunodeficiency: the role of the interleukin-2 receptor gamma chain as a common gamma chain, gamma c. 807 Aug 18

In this study, we have investigated the IL-2R gamma gene expression in several human embryonic fibroblasts which express other components of the IL-2 receptor (IL-2R). Polymerase chain reaction did not allow us to detect IL-2R gamma transcripts in these cells but the functionality of the IL-2R alpha beta was not affected. Indeed, in the human IL-2R alpha+beta+gamma- embryonic lung fibroblasts ICIG-7, IL-2 induced identical phenomena to those previously reported in lymphoid cells: rapid internalization of the IL-2R alpha beta-IL-2 complex, specific phosphorylation of cellular proteins (56 and 38 kDa) and up-regulation of ICAM-1 expression. IL-2 induction of ICAM-1 was only observed in sparse cultures and for IL-2 concentrations over 180 pM. We have also observed, in these fibroblastic cells, the up-regulation of ICAM-2 expression by IL-2, both in sparse and dense cultures. These data show that p64/IL-2R gamma expression in human embryonic fibroblasts does not correlate with the ability of the IL-2R to deliver a biological signal.
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PMID:The IL-2 receptor present on human embryonic fibroblasts is functional in the absence of P64/IL-2R gamma chain. 810 71

The immunologic and genetic analysis of a 14-week-old-male cardigan Welsh corgi puppy that presented with failure to thrive, diarrhea, and intermittent vomiting are described. The lack of palpable lymph nodes, the premature death of a male sibling, and similar clinical signs in a male cousin suggested that a primary immunodeficiency disease might be responsible for his poor clinical condition. Quantitation of serum immunoglobulins revealed low concentrations of IgG and undetectable IgA, yet normal concentrations of IgM. A complete blood cell count showed a slight anemia and lymphopenia. Although the peripheral blood contained a normal percentage of T cells, with an increased CD4:CD8 ratio, they were unable to proliferate in response to phytohemagglutinin (PHA) and/or interleukin 2 (IL-2). Furthermore, following PHA activation, the peripheral blood lymphocytes (PBL) demonstrated a nearly complete lack of IL-2 binding. All of these laboratory findings were identical with our previous findings from dogs with X-linked severe combined immunodeficiency (XSCID) that is due to a mutation in their IL-2 receptor gamma (IL-2R gamma) chain. Examination of the corgi's IL-2R gamma cDNA revealed an insertion of a cytosine following nucleotide 582, resulting in a premature stop codon prior to the transmembrane domain. The insertion also created an EcoO109 restriction enzyme site that enabled us to detect the mutation in the patient's genomic DNA. This new mutation in the IL-2R gamma chain discovered in a cardigan Welsh corgi puppy results in XSCID with similar immunologic abnormalities as observed in dogs with the same disease resulting from a different IL-2R gamma chain mutation.
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PMID:A single nucleotide insertion in the canine interleukin-2 receptor gamma chain results in X-linked severe combined immunodeficiency disease. 857 41


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