Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. 869 Nov 22

In this study we have characterized apoptotic cell death of autoreactive T cells resulting from their interaction with astrocytes and the modulatory effect of steroid hormones. Time kinetics of T-cell activation by interferon (IFN)-gamma-treated astrocytes from neonatal Lewis rats and by professional antigen presenting cells (APCs) from bulk suspensions of thymus or spleen were performed. [3H]Thymidine incorporation of neuritogenic P2- and encephalitogenic myelin basic protein (MBP)-specific T-cell lines declined after 48 h in culture with astrocytes. A similar suppressive effect was observed when T cells were cocultured with thymic APCs and astrocytes. This effect disappeared when astrocytes were separated by a transwell system. After 72 h of culture with astrocytes a mean of 17.5 +/- 12.4% T cells exhibited morphological signs of apoptosis. Apoptosis was identified by light microscopy, and confirmed by electron microscopy, by in situ tailing reaction and by agarose gel electrophoresis. Glucocorticosteroids and oestrogen specifically enhanced T-cell apoptosis within 8 h (69.8 +/- 23.1% and 69 +/- 17.1%, respectively) when added after 72 h to the astrocyte system, but not at earlier time points of T-cell activation or when thymic APCs were used. Glucocorticoid-mediated T-cell apoptosis was inhibited by the steroid-receptor antagonist RU 486. Pregnenolone, lipocortin-1, indomethacin and transforming growth factor-beta did not induce apoptosis in this system. The steroid effect was not associated with CD28, IL-2 receptor, or transferrin-receptor expression, which were equally upregulated on T cells activated by astrocytes or thymic APC as shown by fluorescence activated cell sorting (FACS) analysis. We conclude that astrocytes as CNS-specific APC may render T cells susceptible for induction of apoptotic cell death. Some steroid hormones can markedly enhance this process in vitro and may augment an additional effect of a systemic corticosteroid response in vivo during recovery from autoimmune encephalomyelitis.
 ...
PMID:Antigen presentation by astrocytes primes rat T lymphocytes for apoptotic cell death. A model for T-cell apoptosis in vivo. 880 Sep 54

R24 is a monoclonal antibody directed against the cell surface ganglioside GD3. It can detect GD3 on the surface of a subset of T lymphocytes and can stimulate proliferation and secretion of cytokines in vitro. In the present report, we examined the effects of the R24 antibody upon antigen-specific T cell response, employing an HLA-DR7-specific T cell clonal model. As previously shown, primary stimulation of HLA-DR7-specific alloreactive T cell clones by transfectants expressing HLA-DR7 alone (t-DR7) in the absence of B7 co-stimulation resulted in anergy. Binding of cell surface GD3 on HLA-DR7-specific alloreactive T cell clones with R24 under these anergizing conditions resulted in interleukin-2 (IL-2) accumulation and prevented the induction of alloantigen-specific T cell clonal anergy. Binding of GD3 by R24 also prevented anergy under conditions where B7:CD28 interactions were blocked by CTLA4-Ig. The effect of R24 was abrogated in the presence of a combination of monoclonal antibodies for the alpha and beta chains of the IL-2 receptor (IL-2R) or a neutralizing anti-IL-2 antibody. R24 does not appear to interact directly with the IL-2R since incubation of T cell clones with R24 did not induce early activation of IL-2R associated Jak kinases, Jak1 and Jak3, as was induced following incubation with IL-2. In contrast, incubation of HLA-DR7-specific clones with t-DR7 in the presence of R24 did result in phosphorylation of IL-2R related Jak kinases after 24 h. Our data indicate that the membrane ganglioside GD3 structure recognized by R24 may play an important role in antigen-specific T cell clonal response.
 ...
PMID:R24 anti-GD3 ganglioside antibody can induce costimulation and prevent the induction of alloantigen-specific T cell clonal anergy. 881 60

To study MHC class II-dependent and -independent SAg2 activation and the relative importance of CD80/CD28 costimulation, staphylococcal enterotoxin A (SEA) was presented to T cells as a fusion protein containing the Fab fragment of an mAb directed against the CA215 glycoprotein. Chinese hamster ovary (CHO) cells transfected with HLA-DR4, CA215, and CD80, individually or in combinations, were used as presenting cells. A strong T cell proliferation was obtained when C215Fab-SEA fusion proteins were presented by CHO-DR/CD80 or CHO-CA215/CD80 double transfectants, whereas only low levels of proliferation were seen in the absence of CD80. Large amounts of IL-2, IFN-gamma, and TNF were produced in addition to an increase in IL-2 mRNA as a result of CD80 costimulation. Only approximately 50% of the SEA-reactive T cells responded by expression of IL-2 receptor chains and by blast formation when activated with SEA in the absence of MHC class II. Reverse transcription-PCR-assisted repertoire analysis of SEA-reactive TCR V beta families showed that the CA215-dependent activation involved an expansion of fewer TCR V beta families compared with MHC class II-dependent activation. One-half of the six analyzed TCR V beta families were expanded independently of class II. This indicates that MHC class II has only a partial influence on the TCR V beta repertoire imprinted by SAg. This finding redefines the role of MHC class II in SAg presentation. It is suggested that MHC class II molecules are selected as SAg-binding molecules mainly as a suitable targeting receptor for professional APC expressing costimulatory molecules such as CD80 and CD86.
 ...
PMID:Regulation of superantigen-induced T cell activation in the absence and the presence of MHC class II. 881 90

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.
 ...
PMID:Flow cytometric characterisation of the "false naive" (CD45RA+, CD45RO-, CD29 bright+) peripheral blood T-lymphocytes in health and in rheumatoid arthritis. 885 29

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.
 ...
PMID:Blockade of multiple costimulatory receptors induces hyporesponsiveness: inhibition of CD2 plus CD28 pathways. 887 97

The interaction of co-stimulatory molecules CD80/CD86 on antigen-presenting cells with CD28 on naive CD8+ cytotoxic T (Tc) cells is understood to be critical in the induction of Tc effectors. CD80 is capable of providing signal 2 for the activation of Tc cells, but has no effect if encountered in the absence of specific peptide/MHC complexes (signal 1). We have found that CD80 presented in vitro to resting memory viral-immune or alloimmune Tc cells can provide sufficient stimulus for the generation of effector Tc cells in the absence of specific antigen, the peptide/MHC class I complex. Effector Tc cells generated in vitro from influenza- or class I alloantigen-primed mice by co-stimulation in the absence of antigen require exogenous interleukin (IL)-2 signaling via the cell surface-expressed IL-2 receptor or, under conditions of IL-2 blockade, exogenous IL-7. Activation of memory Tc cells by signal 1 and 2 is independent of IL-2 and IL-7. Although memory influenza-immune Tc cells did respond to CD80 in the absence of antigen, the presence of antigen +CD80 enabled an earlier induction of these Tc cells and they retained their lytic activity in vitro over a longer time period. The capacity of memory Tc cells to be activated by signal 2 alone provides one explanation for the observed heterogeneity of phenotype of memory T cells in vivo and a possible mechanism for the maintenence of memory in the absence of persisting antigen.
 ...
PMID:The generation of memory antigen-specific cytotoxic T cell responses by CD28/CD80 interactions in the absence of antigen. 904 17

To understand mechanism underlying the age-related impairment of T cell functions, changes in the expression of cell surface receptors were examined in T cells after mitogenic stimulation by flow cytometry and results were compared between young and old mice. Before stimulation, no significant difference was observed in the density of TCR alpha beta, CD3, CD122 (IL-2R beta), IL-2R gamma, CD28 and CD95 (Fas) of T cells between young and old mice. As for CD25(IL-2R alpha) and CTLA-4, relative intensity and percentage of positive cells were higher in old than in young mice, although the levels were low compared with those after stimulation. After mitogenic stimulation, increased expression of the density was observed in CD25, IL-2R beta, IL-2R gamma, CD28, CTLA-4 and CD95 and the magnitude of increase was more pronounced in T cells from young than those from old mice. The expression of TCR alpha beta and CD3 decreased after mitogenic stimulation, and the degree of expression quickly recovered to the initial level in young mice, but not in old mice. Lower expression of TCR, IL-2 receptors and co-stimulatory molecules in T cells from old mice could be responsible for the impaired proliferation after mitogenic stimulation.
 ...
PMID:Altered expression of various receptors on T cells in young and old mice after mitogenic stimulation: a flow cytometric analysis. 914 64

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.
 ...
PMID:Microfilarial clearance in loiasis involves elevation of Th1 and Th2 products and emergence of a specific pattern of T-cell populations. 922 84

Stimulation of highly purified primary T lymphocytes through CD2 and CD28 adhesion molecules induces a long-term proliferation, dependent on persistent autocrine secretion of interleukin 2 (IL-2), high and prolonged expression of inducible CD25/IL-2 receptor alpha chain (IL-2Ralpha), and secretion of growth factors such as the granulocyte-macrophage colony-stimulating factor (GM-CSF). CD28 costimulation appears to activate cytokine gene expression through conserved kappaB-related CD28 response (CD28RE) or cytokine 1 (CK-1) elements in addition to canonical NF-kappaB-binding sites. In this report, we assess: 1) the evolution of the expression, over an 8-day time period, of the Rel/NF-kappaB family of proteins in costimulated versus TcR/CD3-stimulated primary T cells; 2) the impact of changes on the in vitro occupancy of GM-CSF kappaB and CK-1, as well as IL-2Ralpha kappaB sites; and 3) the differential regulation of newly synthesized p65 and c-Rel by IkappaB proteins. We show that CD2+CD28 stimulation specifically induces, at maximal T cell proliferation phase, sustained nuclear overexpression of NFKB2 p52 and c-Rel subunits which might rely on long-lasting processing of p100 precursor for p52 and increased neosynthesis of c-Rel. This up-regulation correlates with sustained occupancy of GM-CSF kappaB and CK-1 elements by both proteins. Conversely, these subunits do not appear to bind to the IL-2Ralpha kappaB site. Costimulation, but not TcR/CD3 stimulation, appears supported by sustained down-regulation of both IkappaBalpha and -beta regulators. Furthermore, contrary to p65, c-Rel appears to display little affinity for p105, p100 and IkappaBalpha regulators.
 ...
PMID:Temporal and subunit-specific modulations of the Rel/NF-kappaB transcription factors through CD28 costimulation. 926 7


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>