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)

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

The aim of this study was to quantify and characterize the CD4+ and CD8+, CD45RA+, CD45RO- T-lymphocytes that paradoxically expressed the CD29 bright+ phenotype in health and in rheumatoid arthritis. We further evaluated their clinical implications. Blood samples were obtained from 100 patients with rheumatoid arthritis and 40 age- and sex-matched controls. Cell surface antigens and interleukin-2 (IL-2) binding were detected on CD4+ and CD8+ peripheral blood T-lymphocytes (T-PBL) by three-colour flow cytometry. One-third of the patients were clinically evaluated at the time of blood sampling. In healthy donors, we found 16 +/- 14% of CD29 bright+ cells among CD4+, CD45RA+, RO- T-PBL. These "false naive" CD4+ T-PBL were Leu-8+, and a majority expressed the CD25/p55 receptor (IL-2R alpha chain), while a minority showed the CD11a bright+, CD69+ and/or CD122/p75+ (IL-2R beta chain) phenotype, and few cells were CD31 bright+ and HLA-DR+. In rheumatoid arthritis, their proportion among CD4+, CD45RA+, RO- cells increased to 25 +/- 15% (P < 0.001, compared with controls). In patients, the reductions in CD31 and CD38 expression (P < 0.05 for both), as well as the enhanced CD25 expression (P < 0.001) on CD4+, CD45RA+, RO- T-PBL reflected a more differentiated phenotype. The occurrences of CD25 and CD122 were increased on false naive CD4+ T-PBL (0.01 < P < 0.001); however, the binding of IL-2 remained very low (in contrast to the binding of IL-2 on CD45RO+ T-PBL). Furthermore, a major subset of CD8+, CD45RA+, RO- T-PBL (45 +/- 17% in controls) expressed the CD29 bright+ phenotype. These "false naive" CD8+ T-PBL included a great many of CD11b+, CD28- cells, while a minority showed the HLA-DR+, CD69+ and/or CD122+ phenotypes. Patients with low levels of IgM rheumatoid factors (IgM-RF; but with active disease) had an elevated proportion of CD45RA+, RO- cells among the CD8+ T-PBL, in part due to an increased proportion of false naive cells (P < 0.05). In patients, the false naive CD8+ T-PBL showed down-regulated CD11b and an increased expression of IL-2 receptor chains (CD25 and CD122; 0.05 < P < 0.01), but without a significant increase in IL-2 binding. More CD69 on false naive CD8+ T-PBL was found in patients with high levels of IgM-RF (P < 0.005 compared to patients with low IgM-RF). Finally, both false naive CD4+ and CD8+ T-PBL correlated with the clinical process and outcome variables (0.05 < P < 0.01). The levels of activated false naive (CD4+ T-PBL (CD25+ and/or CD122+) or CD8+ T-PBL (CD69+ and/or CD122+) were associated with clinical parameters of disease activity (0.05 < P < 0.01). Thus, in rheumatoid arthritis, false naive T-PBL showed important qualitative differences. The levels of activated false naive T-PBL could be particularly interesting for monitoring disease evolution.
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PMID:Flow cytometric characterisation of the "false naive" (CD45RA+, CD45RO-, CD29 bright+) peripheral blood T-lymphocytes in health and in rheumatoid arthritis. 885 29

Diethylcarbamazine (DEC) induced clearance of microfilaraemia in loiasis is associated with severe posttreatment reactions. To define the switch from hypo- to hyper-responsiveness associated with DEC treatment, phenotypic alterations of T-lymphocytes, characterized by flow cytometry, and cytokines, determined by enzyme linked immunosorbent assay, were monitored in a microfilaraemic patient. In contrast to reports on onchocerciasis and lymphatic filariases, no elevation of interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha was observed. The most severe side effects coincided with an elevation of interferon (IFN)-gamma on day 3, followed by IL-10, transforming growth factor (TGF)-beta 2 and macrophage inflammatory protein-1 alpha (MIP-1 alpha) peaking on day 5. Phenotypically, T-cell activation markers CD38, CD54 and CD25 were significantly expressed before treatment, with high CD38 expression still existing one year after clearance of microfilaraemia. Treatment-related increases were observed with anti-CD122, anti-HLA-DR and anti-CD69. CD28 was expressed before treatment on almost 100% of CD4+ and CD8+ T cells and dropped to 20% by day 5, reaching again baseline levels on day 21. Furthermore, there emerged 20% TCR alpha beta+/CD3+ T cells and 10% anti-beta V5(c)+ T cells, altogether indicating a specific pattern of T-helper (Th) 1 and Th2 cytokines as well as expansion of certain pauciclonal T-cell populations in response to microfilarial clearance.
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PMID:Microfilarial clearance in loiasis involves elevation of Th1 and Th2 products and emergence of a specific pattern of T-cell populations. 922 84

The impairment of interleukin-2 (IL-2) production occurs very early after human immunodeficiency virus (HIV) infection as a consequence of the quantitative depletion of Th1 cells. Despite the shift in cytokine production, most individuals develop an oligoclonal expansion of major histocompatibility complex restricted, HIV-specific CD8+ cytotoxic T lymphocytes (CTL) in different organs, suggesting that other cytokines replace IL-2 in initiating the tissue infiltration of CD8+ T cells. In this study we show that IL-15, a product of monocyte-macrophages and non-T cells and which has overlapping biological activities with IL-2, is involved in local cell networks accounting for the activation and expansion of CD8+ T-cell pools in a highly affected organ, ie, the lung. IL-15 induced proliferation of T cells obtained from the lower respiratory tract of HIV-infected patients with T-cell alveolitis and severe depletion of CD4+ T cells. Lung lymphocytes were CD45R0+/CD8+ T cells spontaneously expressing activation markers (CD69 and HLA-DR) and equipped with the receptorial subunits which bind IL-15, notably the beta and gamma chains of the IL-2 receptor (IL-2R) and the recently identified IL-15 binding-protein termed IL-15R alpha. Similar phenotypic findings were obtained after incubation of normal T cells with IL-15, which induced CD8+ T cells to express activation markers and to proliferate. The block of the IL-2R beta/IL-2R gamma complex with specific monoclonal antibodies abolished the T-cell stimulatory activity of IL-15 while the combination of IL-15 and tumor necrosis factor-alpha upregulated the proliferative response of lung T lymphocytes. The hypothesis that the tissue growth of lung CD8+ lymphocytes may involve cytokines produced from cells other than T lymphocytes was confirmed by the evidence that pulmonary macrophages expressed high levels of IL-15 and that anti-IL-15 antibodies inhibited the accessory function of alveolar macrophages on mitogen-induced CD8+ T-cell proliferation. Together, these results suggest that macrophage-derived cytokines produced at sites of T-cell infiltration play a role in the activation of HIV-specific CD8+ T-cell-mediated immune response.
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PMID:Interleukin-15 triggers activation and growth of the CD8 T-cell pool in extravascular tissues of patients with acquired immunodeficiency syndrome. 924 43

An acute neutrophilic lung injury was compared in Balb/c normal and nu/nu (nude) mice to assess the role of T lymphocytes in the resolution of acute pulmonary neutrophilic inflammation following the administration of endotoxin. Maximal neutrophilic infiltration occurred on day 1 post-endotoxin treatment and declined to near normal levels by day 5. In contrast, the percentage of lymphocytes in the bronchoalveolar lavage (BAL) fluid increased from 1.8% on day 1 post-endotoxin to greater than 11% on days three and five, during which time neutrophil resolution was occurring. On days 1-5 after endotoxin administration, approximately 40% of the CD4 lymphocytes expressed the cell surface activation marker, CD69. Despite being CD69+, CD4 cells did not express the high affinity IL-2 receptor chain, CD25, to any significant extent on any of the days studied. To assess the contribution of T cells to the rate of clearance of neutrophils from the BAL, normal and nude Balb/c mice were compared for the percentage of neutrophils following nasal administration of endotoxin. Endotoxin-treated nude mice did not demonstrate significant differences in either the total white blood cell counts or in the clearance of neutrophils from the BAL, as compared to normal Balb/c mice. These data indicate that the influx of activated T cells during the resolution of neutrophilic pneumonitis does not contribute to the rate of neutrophil clearance during acute lung injury.
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PMID:Role of T-lymphocytes in the resolution of endotoxin-induced lung injury. 924 70

Although previous studies have shown that 50-200 antigen-major histocompatibility complex complexes (Ag-MHC) are sufficient to stimulate significant secretion of interleukin (IL)-2 from MHC class II-restricted T cell hybridomas, there have been no studies of this nature on more physiologically relevant T cell populations. In this study we have analyzed the ligand requirements for stimulation of responses from naive and previously primed T cells derived from T cell receptor (TCR)-transgenic animals whose TCR is specific for the pigeon cytochrome c (PCC) 88-104 peptide presented by I-Ek. Primed T cells were as sensitive as the previously reported T cell hybridomas, requiring about 100 Ag-MHC complexes to synthesize readily detectable quantities of IL-2, whereas naive T cells required 15 times more ligand to produce equivalent quantities of IL-2. Similarly, primed T cells required about 40 Ag-MHC complexes to produce a significant proliferative response, whereas naive T cells required about 400 complexes. In contrast to these results, naive and primed T cells showed similar ligand requirements when early events in the T cell activation pathway were analyzed; i.e. TCR down-modulation, CD69 and CD25 expression, and blast transformation. A further analysis of IL-2 and IL-2R expression indicated: 1) The first synthesis of IL-2 was detected at the same ligand concentration in both primed and naive T cells, but primed T cells made much more IL-2 as the ligand concentrations increased; 2) primed T cells expressed about fivefold more IL-2 receptor (R) than naive T cells, despite the fact that the antigen dose-response curves with respect to the percentage of cells expressing IL-2R were identical. These results suggest that naive and primed T cells have the same threshold with respect to the number of Ag-MHC complexes required to initiate T cell activation, but that due to the inefficient expression of IL-2 and IL-2R, engagement of more complexes is needed to enable naive T cells to synthesize the necessary amounts of these two molecules to allow T cells to go through a complete cycle of replication.
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PMID:The minimal number of antigen-major histocompatibility complex class II complexes required for activation of naive and primed T cells. 946 19

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

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

The activation status of T lymphocytes and the presence of various cytokines in ascitic fluid were examined to test peritoneal immunity in women with ovarian malignancies. Peripheral blood and peritoneal fluid were collected from 12 patients with primary ovarian cancer with ascites and 27 normal control subjects during laparoscopic examination. Lymphocyte subpopulations and the expression of activation markers on T lymphocytes were analyzed by dual-color flow cytometry. The concentrations of various cytokines and soluble interleukin (IL)-2 receptor-alpha were measured. CD8 T lymphocytes were the main component of peritoneal lymphocytes. CD69 and HLA-DR, but not CD25, were highly expressed on peritoneal T lymphocytes compared to those in peripheral blood. In ascitic fluid of ovarian malignancies, CD4 T lymphocyte concentrations were further decreased, resulting in a decreased CD4/CD8 ratio. Decreased expression of CD69 and CD25 was also noted on T lymphocytes from ascites compared with T lymphocytes in normal peritoneal fluid. IL-1b, tumor necrosis factor-alpha, IL-6, and soluble IL-2 receptor-alpha concentrations were increased significantly in the ascitic fluid of women with ovarian cancer. The decrease in activation markers on T lymphocytes is suggestive of an immunosuppressive state, despite the presence of abundant stimulatory cytokines. The immunosuppression may be multifactorial, attributed, in part, to the increased concentrations of soluble IL-2 receptor-alpha and other inhibitors.
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PMID:T lymphocytes and cytokine production in ascitic fluid of ovarian malignancies. 1006 70

A previously undefined phenotype of CD8(+) cells that appears to represent in vivo activated CTL precursors (CTLP*) has been identified in the spleens of C57Bl/6 mice responding to a P815 tumor allograft. This population was first evident by the transient expression of very high levels of CD28 and CD44 on day 5 of the allograft response and reached maximal levels on days 7 and 8 before declining on day 9. A transient increase in CD69 expression was also observed on these cells on day 5. In contrast, CTL effectors (CTLE), identified by their CD8(+)CD44(hi)CD62LloCD45RBlo phenotype, were not appreciably detected in the spleen until day 8 and reached maximal levels on day 10. Further characterization of CTLP* on day 7 revealed that they represented blasting cells by increased light scatter and also expressed very high levels of CD54 but not CD122, CD152, or CD154. In addition, the cells had already up-regulated CD49d, asialo GM1, CD11a, and CD95L, and down-regulated their expression of CD62L. A small percentage of these cells also expressed CD25. Day 7 CTLP* sorted on the basis of their CD44(xhi) and CD54(xhi) phenotype did not exhibit cytolytic activity in a standard chromium release assay but became cytotoxic when they were cultured in the presence of exogenous murine IL-2 for 5 days. Granzyme B activity, however, was detected in CTLP* on day 7 at levels equivalent to CTLE on day 10. In order to establish a potential precursor relationship between CTLP* and CTLE, mice were treated with various doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a chemical that has been shown to dose-dependently suppress the in vivo generation of CTLE to P815 tumor cells by altering an early stage of CTLP activation. Results indicated that CTLP* were suppressed by TCDD on day 7 to the same degree that CTLE were suppressed on day 10. Importantly, for controls and for all doses of TCDD, there were approximately 12.5 CTLE on day 10 for every CTLP* detected on day 7. These results suggested that TCDD acted identically across all doses to inhibit the early stages of activation of CTLP but did not affect the final stages of differentiation and expansion to CTLE. This interpretation supports the previous observation that TCDD exposure had to occur within the first 3 days of the allograft response in order to induce suppression of CTLE activity. Taken together, these results support the conclusion that in vivo activated CTLP can be identified by their unique expression of very high levels of CD44, CD28, and/or CD54 prior to their full maturation and clonal expansion to functional CTLE.
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PMID:Novel phenotype associated with in vivo activated CTL precursors. 1007 61


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