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)

Mouse MHC class I-specific mAbs recognizing the alpha 1/alpha 2, but not those directed against the alpha 3 domain of the molecule, inhibited RNA, protein, and DNA synthesis of splenic T cells in response to stimulation through the TCR/CD3 complex. Similar inhibition was seen with LFA-1-specific mAbs under the same stimulation conditions. The effect of class I- and LFA-1-specific mAbs reflected a decrease of both IL-2 and IFN-gamma synthesis and IL-2 receptor alpha chain induction. IL-2, IL-2 receptor alpha chain, IFN-gamma, c-fos, c-jun, and c-myc mRNAs were not detected. Activation of AP-1 (c-Fos and c-Jun proteins) and NF-kappa B transcription factors were also inhibited. Inhibition was observed both after treatment of cells in culture and after intravenous injection of Abs in mice. Although bulk phosphorylation was inhibited, early tyrosine phosphorylation and calcium ion influx were normally induced. Protein phosphatase inhibitors did not reverse this inhibition, ruling out an enhanced activation of these enzymes in the observed inhibition. Cell surface expression of one of early PKC activation marker, CD69 was also inhibited. Phorbol esters that directly activate PKC prevented inhibition. Thus, class I molecules are implicated in signal transduction involved at an early stage for T cell activation in a manner that suggests their implication in accessory signal transmission that contributes to the regulation of PKC activity.
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PMID:MHC class I molecules are implicated in costimulatory signals during TCR/CD3-induced activation. 859 31

The purpose of this study was to determine the short-term and long-term effects of repeated daily administration of low dose anti-CD3 monoclonal antibody (mAb) on CD4+ and CD8+ T cell number and function. Daily (7 days) administration of low doses (5 microg) of mitogenic (whole) or nonmitogenic (F(ab')2, fragments) anti-CD3 mAb resulted in depletion of CD4+ and CD8+ T cells in both lymph node and spleen that, in the case of whole mAb, persisted for several months in thymectomized animals. CD3+ cells obtained from thymectomized animals treated with whole but not F(ab')2 fragments of anti-CD3 mAb demonstrated decreased proliferation to anti-CD3 mAb in vitro (on a per cell basis as compared with control animals). Although purified CD4+ cells from animals treated with whole mAb demonstrated only slightly decreased proliferative responses to anti-CD3 mAb in vitro, purified CD8+ cells demonstrated an almost complete loss of their proliferative response. Studies in thymectomized animals demonstrated that the profound CD8+ cell hyporesponsiveness persisted for at least 5 months after anti-CD3 treatment. These effects were not observed in nonthymectomized animals, however, suggesting that recovery of CD8+ T cell function is caused by repopulation of lymphoid organs by thymic-derived CD8+ T cells. Additional studies with purified CD8+ cells from anti-CD3 mAb-treated animals indicated that the hyporesponsiveness was not caused by alterations in T cell receptor (TCR) expression. However, proliferative responses of anergic CD8+ T cells to phorbol ester and ionomycin were comparable to those of control CD8+ T cells. After in vitro stimulation, CD8+ cells from anti-CD3 treated animals did not produce interleukin (IL)-2, and although they retained their ability to upregulate IL-2 receptor expression (albeit reduced by about 50% compared with CD8+ cells from control animals), proliferative responses were not restored by addition of exogenous IL-2. In addition to IL-2 receptor expression, CD8+ cells from anti-CD3-treated animals also demonstrated an ability to upregulate CD44 and LFA-1 expression upon reexposure to anti-CD3 mAb in vitro. In conclusion, treatment with daily administration of low doses of whole or F(ab')2 fragments of anti-murine CD3 mAb induces significant T cell depletion in secondary lymphoid organs and does not seem to alter CD4+ proliferative responses in vitro, but whole mAb (and not F(ab')2 fragments) profoundly suppresses CD8+ proliferative responses. The profound hyporesponsiveness of CD8+ T cells induced by whole anti-murine CD3 mAb (1)persists for at least persists for at least several months, (2) is characterized by decreased IL-2 production and responsiveness to IL-2, and (3) recovery of CD8+ cell function is likely mediated by repopulation of lymphoid organs by thymic-derived CD8+ cells.
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PMID:In vivo administration of anti-murine CD3 monoclonal antibody induces selective, long-term anergy in CD8+ T cells. 860 86

Trypanosoma cruzi infection in humans and experimental animals often results in a chronic heart and gut inflammation and a dysfunction known as Chagas' disease. Previous studies have shown that the cellular infiltrate in the hearts of animals with chronic Chagas' disease consists mainly of CD8+ T cells. In this study, we have used immunohistochemical techniques to further characterize the immunological nature of chagasic heart lesions in three murine models of experimental Chagas' disease. Double-staining immunohistochemistry revealed that 10-30% of the infiltrating CD8+ T cells in the hearts of infected mice expressed the activation molecules, IL-2 receptor and CD44. In addition, large numbers of cells producing TNF-alpha, TGF-beta, IL-1 alpha, and IL-6 were consistently observed in the heart lesions, appearing during the acute infection and persisting throughout the chronic stage of infection (> 300 days). In contrast, IFN-gamma- and IL-10-producing cells were detected in relatively low numbers and only transiently between approximately 3 and 9 weeks postinfection. Cells producing IL-2, IL-4, and IL-5 were not observed in the hearts of mice at any point during the infection. The appearance of cytokine-producing cells in the hearts correlated with an increased local expression of class I and class II MHC molecules and adhesion molecules (ICAM-1, LFA-1, VLA-4, and VCAM-1). The results of this study suggest that the chronic inflammation in chagasic hearts is highly active and associated with a stable immunological pattern extending from the early acute stage of the infection through the late chronic stage. The pattern of cytokine production in heart is distinct from that observed in lymphoid organs and is not suggestive of an association between particular classes of cytokines and disease development. Instead it appears that both inflammatory and anti-inflammatory cytokines determine the pattern of the cellular response and the severity of disease in T. cruzi infection.
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PMID:Persistent production of inflammatory and anti-inflammatory cytokines and associated MHC and adhesion molecule expression at the site of infection and disease in experimental Trypanosoma cruzi infections. 893 70

The infiltration of pancreatic islets by mononuclear cells is the hallmark of the development of insulin dependent diabetes mellitus (IDDM) in the NOD mouse, an animal model for human IDDM. The aim, of this study was to correlate adhesion molecule expression with the degree of islet infiltration and to compare Th1- and Th2-driven islet inflammation. Cryostat sections of NOD mouse pancreata before and after diabetes development were analysed by semiquantitative immunohistochemistry. NOD mouse islets did not show the expression of ICAM-1, LFA-1, L-selectin and VCAM-1 prior to infiltration by mononuclear cells. Furthermore, islets with early stage insulitis (grade 1, periinsular location of small infiltrates) still were devoid of adhesion molecule expression. ICAM-1 and LFA-1 were first demonstrable in islets with strong periinsular infiltrates (insulitis grade 2) while L-selectin and VCAM-1 were only seen in islets with mild or strong intraislet infiltration (grade 3-4). Adhesion molecules were demonstrable in areas of macrophage and T-lymphocyte infiltrates but not in adjacent endocrine islet tissue. Islets of all infiltration stages contained Th2 lymphocytes (positive for IL-4). Substantial numbers of Th1 cells (positive for IFN-gamma, TNF-alpha, IL-2 and/or IL-2 receptor) were observed only after acceleration of diabetes development by a single injection of cyclophosphamide (250 mg/kg i.p.). Interestingly, the adhesion molecule expression pattern in islets with "Th1' versus "Th2 insulitis' was not different. In conclusion, the expression of adhesion molecules in islets during the development of autoimmune diabetes does not precede mononuclear infiltration but probably occurs in response to the activation of initial small infiltrates. ICAM-1 and LFA-1 expression is seen prior to L-selectin and VCAM-1. However, adhesion molecule expression during Th1 versus Th2 cell infiltration is very similar, suggesting similar adhesion molecule requirements of the two Th subsets.
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PMID:Differential expression of ICAM-1 and LFA-1 versus L-selectin and VCAM-1 in autoimmune insulitis of NOD mice and association with both Th1- and Th2-type infiltrates. 893 79

Indolent, primary cutaneous T-cell lymphomas (CTCL) are characterized by hyper-proliferation of malignant T-helper cells in the skin with a favorable prognosis in the early stages. Cytotoxic T cells (CTLs) are believed to be of major importance for tumor surveillance, but there is not yet sufficient evidence for a systemic anti-tumor response in mycosis fungoides (MF). On the contrary, there are hints of systemic immunodepression. We wondered whether signs of a systemic anti-tumor response were demonstrable in peripheral blood of patients with MF and CD30+ pleomorphic T cell lymphoma. Using multiparameter flow cytometry, we investigated blood samples from 39 CTCL patients at different stages and compared them with those from patients with psoriasis, atopic dermatitis, and healthy volunteers. In CTCL patients, an elevated number of lymphocytes expressing natural killer cell markers were found, as well as considerable T-cell activation, indicated by increased percentages of T cells expressing HLA-DR, IL-2 receptor alpha-chain, and transferrin receptor. The CD8+ T cells, which were the most strongly activated T-cell subset, were of polyclonal origin, as shown by their usage of different T-cell receptor families. The enhanced expression of activation antigens was associated with an increased proportion of CD8+ T cells with high expression of the adhesion molecule LFA-1, demonstrating the capacity for migration of these cells. These CD8+ effector cells are suspected to be CTLs and may be responsible for the favorable prognosis of indolent, primary CTCL. Interestingly, a stage-dependent decrease in T-cell activation antigen expression was observed, suggesting the development of a lack in tumor surveillance in advanced MF stages. Further investigations are necessary to verify whether any of the parameters determined are of predictive value for prognosis and response to therapy in CTCL.
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PMID:Enhanced expression of T-cell activation and natural killer cell antigens indicates systemic anti-tumor response in early primary cutaneous T-cell lymphoma. 912 26

The migration of lymphocytes through primary cultures of rat brain microvascular endothelial cell monolayers was examined in vitro by time-lapse videomicroscopy. Antigen-specific T cell line migration was dependent on the duration of culture (post-antigen stimulation) with exogenous interleukin-2 (IL-2). Peak migration (approximately 50% of T-cells during the 4 h migration assay) occurred after 4 days of culture with IL-2 but did not coincide with maximal expression of LFA-1, VLA-4 or the IL-2 receptor. On unstimulated endothelia antibody blockade of LFA-1 or ICAM-1 inhibited T-cell line migration to 8.0% and 6.8% of control values, respectively, whereas blocking VLA-4 and VCAM-1 had no effect. On IL-beta activated endothelium blocking LFA-1 and ICAM-1 was less effective (24.9% and 27.3% of control values, respectively) and blockade of VLA-4 and VCAM-1 brought about a reduction to 63.0% and 68.3% of controls respectively. Inhibition of IL-2-dependent proliferation with an IL-2 receptor blocking antibody also significantly inhibited T-cell migration to 22.2% of controls. Peripheral lymph node (PLN) lymphocytes could also be induced to migrate through untreated cerebral endothelial cell monolayers by cross-linking CD3 which was also time and IL-2-dependent with maximal migration (22.7%) occurring after three days in the presence of exogenous IL-2. Blocking LFA-or ICAM-1 resulted in a significant reduction in migration across IL-1 beta-activated endothelial cells to 17.4% and 20.9% of control values respectively although blocking the VLA-4/VCAM-1 interaction had no significant effect. Activation of PLN lymphocytes with concanavalin A for up to 5 days did not induce migration but when left in contact with the endothelial monolayer for 24 h migration reached 31.0%. These studies indicate that T-cells require a combination of signals to trigger the migratory phenotype which is necessary to enable them to penetrate the blood-brain barrier.
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PMID:Factors controlling T-cell migration across rat cerebral endothelium in vitro. 914 41

Interleukin-15 (IL-15) is a recently described cytokine with IL-2-like stimulating activities on T lymphocytes and natural killer (NK) cells. IL-15 mediates its function through the beta- and gamma-chains of the IL-2 receptor. In this work, we have investigated the effect of IL-15 on the directional migration of NK cells in chemotaxis assays and on the ability of NK cells to bind to vascular endothelium. IL-15 (10-20 ng/mL) had chemotactic effects on freshly isolated resting NK cells as well as on long-termed IL-2-cultured NK cells. A checkerboard experiment demonstrated that migration in response to IL-15 was observed only in the presence of a positive gradient (chemotaxis). Overnight treatment of freshly isolated NK cells with IL-15 (10-20 ng/mL) augmented their binding to cultured endothelial cells (EC) in vitro, especially to resting EC. IL-15-activated NK cells bound to resting and tumor necrosis factor-activated EC by use of LFA-1/ICAM-1 and VLA-4/VCAM-1 adhesion pathways, essentially as untreated NK cells do. The fact that IL-15 increased NK cell binding to ICAM-1-transfected NIH-3T3 fibroblasts, together with the finding that IL-15 did not increase binding to extracellular matrix proteins, where the major molecules involved are VLA proteins, indicated that IL-15 primarily stimulates LFA-1-dependent adhesion. By increasing NK cell adhesion to vascular endothelium and migratory response, IL-15 is an important determinant of NK cell recruitment in tissues.
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PMID:IL-15 is chemotactic for natural killer cells and stimulates their adhesion to vascular endothelium. 920 Dec 64

It has been reported that allograft rejection is mediated by a variety of adhesion molecules. Using a corneal allograft model in mice, we studied the role of very late antigen (VLA)-4 and leukocyte function-associated antigen (LFA)-1 adhesion molecules in corneal allograft rejection and the effects of monoclonal antibodies (mAbs) to them in suppressing corneal rejection. C3H/He donor corneas were transplanted into BALB/c corneal beds. The allografted mice were treated with a control mAb (M18/2), mAbs to VLA-4, or LFA-1 or their combination by i.p. injection until day 7. The expression of VLA-4, LFA-1, major histocompatibility complex (MHC) class II antigens, interleukin (IL)-2, IL-2 receptor and interferon gamma (IFNgamma) in the grafted cornea were studied immunohistochemically. Cytotoxic T lymphocyte (CTL) responses to donor alloantigens were assessed. The skins from a syngeneic donor or a third-part strain were transplanted 8 weeks after the initial keratoplasty onto the mice treated with anti-LFA-1 plus anti-VLA-4 mAbs. Fourteen of 16 allografts in non-treated mice and control mAb-treated mice became opaque by 2 weeks after transplantation. At 2 weeks, non-treated allografts showed expression of MHC class II antigens on keratocytes and mononuclear cells at the host-graft junction. Also, mononuclear cells expressing VLA-4, LFA-1, IL-2, IL-2 receptor and IFNgammawere present in the stroma at the host-graft junction. The allografts treated with either anti-VLA-4 or anti-LFA-1 alone, or anti-VLA-4 plus anti-LFA-1 remained transparent for more than 2 weeks, and the survival rates at 14 weeks was 0%, 16.7%, and 75.0%, respectively. The combined use of anti-VLA-4 and anti-LFA-1 mAbs prolonged graft survival significantly (P<0.05) at 14 weeks as compared with anti-LFA-1 mAb alone. At 3 weeks, CTL responses to donor alloantigens were depressed in mice treated with either anti-LFA-1 alone or anti-LFA-1 plus anti-VLA-4. Specific prolongation of donor-syngeneic skin was observed after treatment with the combination of these two mAbs. These results indicate that VLA-4 and LFA-1 have important roles in rejection process of corneal allografts, and that the combined use of mAbs to these molecules has remarkable effects on inducing alloantigen-specific immunosuppression in corneal transplantation.
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PMID:Specific immunosuppression of corneal allograft rejection by combination of anti-VLA-4 and anti-LFA-1 monoclonal antibodies in mice. 923 69

Induction of Fas-mediated activation-induced cell death in antitumor T cells has been hypothesized to permit tumor escape from immune destruction. Several laboratories have proposed that expression of Fas ligand (L) by tumor is the basis for this form of T cell tolerance. In this study, we characterized murine tumor-infiltrating lymphocytes (TIL) for activation status, cell cycle status, level of apoptosis, cytokine secretion, and proliferative capacity. TILs express multiple activation markers (circa CD69, CD95L, CD122, and LFA-1) and contain IL-2 and IFN-gamma mRNAs, but are neither cycling nor apoptotic in situ. In addition, TIL are dramatically suppressed in proliferative response and do not secrete IL-2 and IFN-gamma. However, upon purification and activation in vitro, TIL secrete high levels of IL-2 and IFN-gamma, enter S phase, and then die by Fas-mediated apoptosis. Activation by injection of anti-TCR Ab or IL-2 into tumor-bearing mice induced TIL entrance into S phase preceding apoptosis, showing that TIL have functional TCR-mediated signal transduction in situ. Our data demonstrate that TIL, not tumor, express both Fas and FasL, are arrested in G(1), do not secrete cytokine in situ, and, upon activation in vitro and in vivo, rapidly die by activation-induced cell death.
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PMID:CD8+ tumor-infiltrating lymphocytes are primed for Fas-mediated activation-induced cell death but are not apoptotic in situ. 1134 25

TGF-beta1 plays an important role in the maintenance of immune homeostasis and self-tolerance. To determine the mechanism by which TGF-beta1 prevents autoimmunity we have analyzed T cell activation in splenic lymphocytes from TGF-beta1-deficient mice. Here we demonstrate that unlike wild-type splenic lymphocytes, those from Tgfb1(-/-) mice are hyporesponsive to receptor-mediated mitogenic stimulation, as evidenced by diminished proliferation and reduced IL-2 production. However, they have elevated levels of IFN-gamma and eventually undergo apoptosis. Receptor-independent stimulation of Tgfb1(-/-) T cells by PMA plus ionomycin induces IL-2 production and mitogenic response, and it rescues them from anergy. Tgfb1(-/-) T cells display decreased CD3 expression; increased expression of the activation markers LFA-1, CD69, and CD122; and increased cell size, all of which indicate prior activation. Consistently, mutant CD4(+) T cells have elevated intracellular Ca(2+) levels. However, upon subsequent stimulation in vitro, increases in Ca(2+) levels are less than those in wild-type cells. This is also consistent with the anergic phenotype. Together, these results demonstrate that the ex vivo proliferative hyporesponsiveness of Tgfb1(-/-) splenic lymphocytes is due to prior in vivo activation of T cells resulting from deregulated intracellular Ca(2+) levels.
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PMID:TGF-beta 1 regulates lymphocyte homeostasis by preventing activation and subsequent apoptosis of peripheral lymphocytes. 1270 39


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