Gene/Protein Disease Symptom Drug Enzyme Compound
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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 have investigated several aspects of gamma delta T cells in sheep. gamma delta T cells of sheep express a unique transmembrane protein termed T19 but lack the expression of particular cell-surface molecules such as CD2, CD4 and CD8 which are typically associated with alpha beta T cells. The majority of gamma delta T cells isolated from animals of all ages examined lacked the expression of CD45RA. A faster rate of activation by gamma delta T cells compared to either CD4 or CD8 T cells was seen in the time-course of IL-2 receptor alpha chain (CD25) cell-surface expression. All gamma delta T cells expressed the CD25 protein within 8 hr of activation whereas the majority of CD4 or CD8 T cells did not express CD25 until 24 hr post-concanavalin A (Con A) stimulation. This difference in the rate of expression of activation molecules was not restricted to CD25, as a similar trend was seen with cell-surface expression of major histocompatibility complex (MHC) class II molecules. We have used the distinct phenotypic profile of ovine gamma delta T cells to purify these cells by positive selection via the T19 molecule to assess their in vitro proliferative response to various antigens. Routinely, cell populations comprising more than 93% gamma delta T cells with yields of approximately 55% were obtained. Purified gamma delta T cells were capable of responding to Mycobacterium tuberculosis antigen in a primary and secondary in vitro proliferation assay and to ovalbumin in a secondary response. Ovine gamma delta T cells showed little, if any, proliferative response to allogeneic stimulator cells.
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PMID:Antigen recognition and activation of ovine gamma delta T cells. 792 94

The role of the Legionella pneumophila protease in the pathogenesis of Legionnaires' disease is unclear. In this study, we assessed the effect of purified protease preparations on human recombinant interleukin-2 (IL-2), the IL-2 receptor, and several additional human T-cell surface proteins to determine whether protease contributes to the virulence of L. pneumophila by interfering with human T-cell activation and function. IL-2-induced proliferation of CTLL-2 cells was inhibited by coincubation with protease (10 to 100 U/ml). Protease at concentrations of > or = 10 U/ml cleaved human recombinant IL-2 as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of reaction mixtures containing 125I-labeled IL-2 and protease. Protease treatment of activated human T cells did not inhibit binding of a monoclonal antibody directed against the alpha subunit of the IL-2 receptor and did not interfere with binding of IL-2 to IL-2 receptors on the lymphocytes. Treatment of blood mononuclear cells or activated T cells with protease (50 U/ml) inhibited the binding of a monoclonal antibody directed against CD4. In contrast, protease treatment did not inhibit the binding of antibodies against CD3, CD8, class II major histocompatibility complex, and the transferrin receptor. Heat inactivation (65 degrees C for 20 min) of the protease or treatment with the metal chelator EDTA ablated the inhibitory effect of the protease. The ability of the protease to degrade IL-2 and cleave CD4 on human T cells suggests that protease may contribute to the pathogenesis of Legionnaires' disease by impeding T-cell activation and immune function.
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PMID:Legionella pneumophila protease inactivates interleukin-2 and cleaves CD4 on human T cells. 833 71

Clonal activation of CD4+ and CD8+ T lymphocytes depends on binding of peptide-major histocompatibility complex (MHC) molecule complexes by their alpha/beta receptors, eventually resulting in sufficient aggregation to initiate second messenger generation. The nature of intracellular signals resulting from such T cell receptor (TCR) occupancy is believed to be independent of the specific structure of the ligand being bound, and to vary quantitatively, not qualitatively, with the concentration of ligand offered and the affinity of the receptor for the peptide-MHC molecule complex. In contrast to the expectations of this model, the analysis of the response of a T helper type 1 clone to mutant E alpha E beta k molecules in the absence or presence of a peptide antigen revealed that peptide inhibited the interleukin 2 (IL-2) response to an otherwise allostimulatory mutant form of this MHC class II molecule. The inhibition was not due to competition for formation of alloantigen, it required TCR recognition of peptide-mutant MHC molecule complexes, and it decreased IL-2 production without affecting receptor-dependent IL-3, IL-2 receptor alpha, or size enlargement responses. This preferential reduction in IL-2 secretion could be correlated with the costimulatory signal dependence of this cytokine response, but could not be overcome by crosslinking the CD28 molecule on the T cell. These results define a new class of TCR ligands with mixed agonist/antagonist properties, and point to a ligand-related variation in the quality of clonotypic receptor signaling events or their integration with other signaling processes. It was also found that a single TCR ligand showed greatly different dose thresholds for the elicitation of distinct effector responses from a cloned T cell population. The observations that changes in ligand structure can result in qualitative alterations in the effects of receptor occupancy and that quantitative variations in ligand density can be translated into qualitative differences in T cell responses have important implications for models of intrathymic selection and control of the results of active immunization.
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PMID:Peptide-major histocompatibility complex class II complexes with mixed agonist/antagonist properties provide evidence for ligand-related differences in T cell receptor-dependent intracellular signaling. 838 51

In this review, we summarize the cellular and molecular events in the rejection of transplanted allografts, as well as the rationale for the evolving techniques to suppress such rejection. Allogenic major histocompatibility complex antigens expressed on the allograft and/or on the "passenger leukocytes" within the graft are the major antigenic stimuli recognized as being foreign by receptors of CD4+/T helper cells of the host. Host macrophages provide a second signal, interleukin (IL) 1, essential to the activation of T helper cells. Subsequent production of IL-2 by T helper cells leads to activation and proliferation of cytotoxic T cells and lymphokine-activated killer cells and the release of IL-4 and IL-6. In addition, IL-2 promotes release of interferon gamma as well as tumor necrosis factor and other proinflammatory cytokines. Therapeutic options to "downregulate" this cascade have gradually evolved from global nonspecific immunosuppressive techniques (total body irradiation, antilymphocyte serum) to increasingly specific modalities currently being studied, including monoclonal antibodies against the IL-2 receptor (thus targeting only vigorously proliferating T cells), antibodies against specific cytokines (interferon gamma, tumor necrosis factor), and now "designer" antibody-toxin conjugate molecules that deliver toxins to selected receptor targets. Finally, work continues toward inducing preoperative antigen-specific (graft) tolerance, including utilization of gene transfection techniques to transfect donor major histocompatibility complex antigens to recipients before surgery, which has been shown to prolong murine cardiac allografts, perhaps by priming specific suppressor cells. Further understanding of the initiation of, and subsequent events in, transplantation rejection will lead to increasingly effective prolongation of graft survival while minimizing adverse effects on the host.
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PMID:Transplant rejection. Mechanisms and treatment. 844 82

The heterogeneity of the thymic stroma has made careful characterization of particular thymic stromal cell types difficult. To this end, we have derived a panel of cloned thymic stromal cell lines from simian virus 40 T antigen (SV40-T antigen) transgenic mice. Based on their analysis with monoclonal antibodies that distinguish among subsets of thymic stroma cells, and on the morphology and ultrastructural features of the different clones, we suggest that our panel includes representatives of the thymic subcapsular cortex or thymic nurse cells (427.1), the deep cortex or cortical reticular cells (1308.1) and the medulla including medullary interdigitating (IDC)-like cells (6.1.1) and medullary epithelial cells (6.1.7). A fifth cell type of undesignated but apparent medullary origin (6.1.11) was also isolated. All of the cell lines constitutively express the SV40 T antigen transgene and the class I antigens of the major histocompatibility complex (MHC), and they can be induced to express MHC class II antigens upon stimulation with recombinant interferon-gamma (IFN-gamma). These cell lines elaborate a factor(s) that induces the proliferation of cells from the fetal liver and bone marrow, but not from the neonatal thymus. A factor(s) elaborated by the 1308.1 cell line also induces the proliferation of fetal thymocytes in the absence of mitogens, phorbol esters or calcium ionophore which is augmented with the addition of recombinant interleukin-2 (IL-2). Analysis by reverse transcription polymerase chain reaction with primers for some mouse cytokines reveals that each of these cell lines contain granulocyte-macrophage colony-stimulating factor (GM-CSF) transcripts and that 1308.1, 6.1.1 and 6.1.7 produce IL-6 mRNA. Cell lines 1308.1 and 6.1.1 also produce IL-7; 6.1.1 produces IL-1 beta and tumor necrosis factor (TNF)-alpha while the 427.1 cell line produces IL-5 and IFN-gamma mRNA. None of the cell lines tested express the IL-2 receptor, IL-2, IL-3, IL-4, TNF-beta or macrophage inflammatory proteins mRNA. Conditioned medium (CM) from 1308.1 and 6.1.11 induced differentiation of cells purified from the mouse fetal liver into granulocytes; 1308.1 CM also induced differentiation of the mouse hematopoietic stem cell line 32DCl3(G) suggesting that the CM contains granulocyte (G)-CSF activity. Each cell line produces GM-CSF but the greatest activity is associated with 1308.1 and 6.1.11 CM. The availability of these well-characterized, functional, cloned thymic stromal cells will allow a more detailed analysis of the role of each cell type in both myeloid and T cell development.
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PMID:Phenotypically diverse mouse thymic stromal cell lines which induce proliferation and differentiation of hematopoietic cells. 850 May 19

Septic complications have been major problems in the management of patients with obstructive jaundice and neonatal jaundice. This study investigates effects of unconjugated bilirubin on lymphocyte-mediated cytotoxicity against human tumor target cells. In vitro exposure of human peripheral blood lymphocytes (PBL) with bilirubin IX alpha in bovine albumin solution resulted in a dose-dependent decrease of both natural killer activity and antibody dependent cellular cytotoxicity (ADCC) activity. Inhibition of both activities correlated with the amounts of intracellular bilirubin. Expression of cell surface CD16, CD56 antigen, and IL-2 receptor beta chain was unchanged in bilirubin-treated PBL as compared to bilirubin-untreated PBL. When bilirubin-treated PBL were cultured with interleukin-2 (IL-2), a dose-dependent decrease of lymphokine-activated killing activity, ADCC activity, and DNA synthesis was observed. Expression of CD56 antigen and IL-2 receptor alpha chain was unchanged in bilirubin-treated PBL following IL-2 stimulation as compared to bilirubin free control. These results suggest that bilirubin inhibits major histocompatibility complex-unrestricted cytotoxicity in both unstimulated and IL-2 stimulated lymphocytes. These observations may help explain the increased susceptibility to infection observed in hyperbilirubinemic patients.
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PMID:Unconjugated bilirubin inhibits in vitro major histocompatibility complex-unrestricted cytotoxicity of human lymphocytes. 863 40

Human CD4+ T cells, activated by allogeneic monocytes in a primary mixed lymphocyte reaction in the presence of exogenous interleukin (IL) 10, specifically failed to proliferate after restimulation with the same alloantigens. A comparable state of T cell unresponsiveness could be induced by activation of CD4+ T cells by cross-linked anti-CD3 monoclonal antibodies (mAbs) in the presence of exogenous IL-10. The anergic T cells failed to produce IL-2, IL-5, IL-10, interferon gamma, tumor necrosis factor alpha, and granulocyte/macrophage colony-stimulating factor. The IL-10-induced anergic state was long-lasting. T cell anergy could not be reversed after restimulation of the cells with anti-CD3 and anti-CD28 mAbs, although CD3 and CD28 expression was normal. In addition, restimulation of anergized T cells with anti-CD3 mAbs induced normal Ca2+ fluxes and resulted in increased CD3, CD28, and class II major histocompatibility complex expression, indicating that calcineurin-mediated signaling occurs in these anergic cells. However, the expression of the IL-2 receptor alpha chain was not upregulated, which may account for the failure of exogenous IL-2 to reverse the anergic state. Interestingly, anergic T cells and their nonanergic counterparts showed comparable levels of proliferation and cytokine production after activation with phorbol myristate acetate and Ca2+ ionophore, indicating that a direct activation of a protein kinase C-dependent pathway can overcome the tolerizing effect of IL-10. Taken together, these data demonstrate that IL-10 induces T cell anergy and therefore may play an important role in the induction and maintenance of antigen-specific T cell tolerance.
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PMID:Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. 869 Nov 22

The antigen-presenting role of major histocompatibility complex (MHC) Class I molecules in the activation of appropriately restricted T cells is well documented. Now growing evidence indicates that MHC Class I molecules can, in addition, exert a regulatory effect and influence the resulting immune responses. In this report we show that a monoclonal antibody (mAb) directed against a conserved region of the human leukocyte antigens (HLA)-A, -B, and -C was able to inhibit proliferation of human peripheral blood mononuclear cells induced by the superantigen, Staphylococcus enterotoxin A. While anti-HLA inhibition was associated with a decrease in IL-2 receptor (IL-2R) expression, the addition of exogenous IL-2 did not restore the proliferative response in the presence of anti-HLA mAb. The inhibition of DNA synthesis was also associated with a decrease in the expression of the early activation marker CD69. These results suggest a critical role for HLA Class I molecules in the early events of human lymphocyte activation and proliferation as well as in their expression of the IL-2R.
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PMID:Anti-HLA class I antibody inhibits Staphylococcus enterotoxin A (SEA)-induced proliferation of human PBMC. 880 16

T-lymphocyte activation requires engagement of the T cell receptor with antigen-major histocompatibility complex, and simultaneous ligation of costimulatory pathways via the lymphocyte receptors CD2 and CD28/ CTLA4. Anti-CD2 monoclonal antibody (mAb) blocks the interaction of the antigen-presenting cell receptor CD48 with its ligand CD2, whereas CTLA4Ig binds with high affinity to the antigen-presenting cell ligands B7-1 and B7-2, blocking their interaction with CD28/CTLA4. We tested the immunosuppressive effects of simultaneously blocking both costimulatory pathways. Using donor C57BL/6J (H2b) hearts transplanted to CBA/J (H2k) recipients, anti-CD2 mAb plus CTLA4Ig administered at the time of transplantation prolonged cardiac allograft mean survival time to >120 days compared with untreated controls (12.2+/-0.5 days, P<0.01), anti-CD2 mAb alone (24.8+/-1.0 days, P<0.01), or CTLA4Ig alone (55.0+/-2.0 days, P<0.01). Retransplantation of these recipients with donor-specific and third-party grafts demonstrated that hyporesponsiveness and tolerance were achieved. In vitro stimulation of lymphocytes from tolerant recipients with donor-specific alloantigen resulted in normal cytotoxic T lymphocyte and mixed lymphocyte reaction responses, showing that clonal deletion or anergy did not occur, but that graft adaptation or suppression likely helped to maintain long-term graft survival. In vitro combinations of anti-CD2 mAb and CTLA4Ig suppressed the generation of allogeneic cytotoxic T lymphocytes (58%) and the mixed lymphocyte reaction (36%); CTLA4Ig was more effective in this regard and the two agents were not synergistic. Anti-CD2 mAb and CTLA4Ig suppressed mitogen-driven proliferation in differential fashions, suggesting that they affected independent signaling pathways. Anti-CD2 mAb and CTLA4Ig also inhibited interleukin (IL)-2, IL-4, and IL-2 receptor (CD25). These data indicate that anti-CD2 mAb plus CTLA4Ig induces hyporesponsiveness and tolerance. The mechanism is likely related to the initial disruption of independent pathways of T-lymphocyte activation leading to antigen-specific long-term graft survival.
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PMID:Blockade of multiple costimulatory receptors induces hyporesponsiveness: inhibition of CD2 plus CD28 pathways. 887 97

The regulation of human natural killer (NK) cell activation is under the control of a network of regulatory signals provided by cytokines. In the present study, we investigated the functional interaction between interleukin (IL)-4 and two monocyte/macrophage-derived cytokines, IL-12 and IL-15, during the process of NK stimulation. Using freshly isolated human NK cells, we have demonstrated that IL-4 negatively regulates lymphokine-activated killer (LAK) activity induced by IL-15 against the NK-resistant Daudi target cells. In contrast, IL-4 had no effect on IL-12-stimulated LAK generation. The differential effect of IL-4 on NK cell activation by IL-12 and IL-15 correlates with its ability to increase or to down-regulate the level of tumor necrosis factor-alpha and interferon-gamma release by NK cells, respectively. In contrast, endogenous transforming growth factor-beta 1 does not appear to be involved in the IL-4 regulatory pathway. Furthermore, while IL-4 was found to decrease the basal expression of the IL-2 receptor beta subunit utilized by IL-15, it had no effect on the expression of the beta 1 chain of the IL-12 receptor compared to untreated cells. Northern blot analysis indicated that the IL-4 regulatory effect on NK lytic function was associated with its capacity to down-regulate granzyme B and perforin gene transcription in response to IL-15 and its failure to affect the expression of both gene's in response to IL-12. Together, these data suggest the existence of a distinct cross-talk between IL-4 and IL-15 or IL-12 signaling pathways during the regulation of human non-major histocompatibility complex-restricted cytotoxicity.
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PMID:Differential regulation of interleukin-12- and interleukin-15-induced natural killer cell activation by interleukin-4. 892 63


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