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 bacterial exotoxins staphylococcal enterotoxin A and B (SEA and SEB) mediate disease through their effects on T lymphocytes. In this manuscript we have demonstrated that both SEA and SEB can directly activate purified T cells in the absence of accessory cells as determined by a transition from G0 to G1 and induction of IL-2 receptor expression. However, neither SEA nor SEB alone was sufficient to result in T-cell proliferation. The induction of T-cell proliferation by SEB or SEA required the addition of a second costimulatory signal. This could be provided by either accessory cells or monoclonal antibody stimulation of CD28. As previously reported, T-cell proliferation induced by enterotoxin in the presence of accessory cells was partially inhibited by a blocking antibody against class II MHC. In contrast, in purified T cells when costimulation was provided through CD28, proliferation was not inhibited by class II antibody, and HLA-DR expression was not detectable. In addition, costimulation through CD28 was partially resistant to the effects of cyclosporin A. These results demonstrate that CD28 costimulation is sufficient to induce proliferation of enterotoxin-activated T cells, and that this effect is independent of class II MHC expression.
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PMID:CD28 and staphylococcal enterotoxins synergize to induce MHC-independent T-cell proliferation. 133 Mar 29

While recent studies in Rhesus monkeys have pointed out the importance of an intact nef gene for the development of acquired immunodeficiency syndrome (AIDS), no biological function has been so far unambiguously attributed to its product. Since Nef has been described to possess GTP-binding properties and to down-regulate CD4 cell surface expression, we looked for evidences of Nef interfering with the transduction of activating signals in human CD4+ T cells. We used a murine leukemia retroviral vector to express the HIV-1BRU nef gene in two permanent tumoral T-cell lines (CEM and Jurkat) and in two nonimmortalized, interleukin-2 (IL2)-dependent, T-cell clones. The single copy recombinant provirus integrated in the genome of these cells directed the synthesis of a 27-kD protein with a half-life greater than 5 h. The levels of expression of cell surface molecules involved in T-cell functions (CD4, CD3, CD28, CD29, IL-2 receptor) were not modified in cell populations expressing Nef. In immunocompetent T-cell clones, cell proliferation and lymphokine production in response to activating stimuli (IL-2, alloantigens, phorbol esters, or antibodies directed against CD2, CD3, CD4, CD28) remained unmodified. Moreover, the presence of Nef did not change the kinetics of human immunodeficiency virus (HIV) infection.
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PMID:Activation pathways and human immunodeficiency virus type 1 replication are not altered in CD4+ T cells expressing the nef protein. 135 46

The effect of the CD28 activation pathway on the immunosuppressive action of CsA was assessed. Human peripheral blood lymphocytes were stimulated with anti-CD3, bryostatin (Bryo) a novel activator of protein kinase C (PKC) and anti-CD28 singly or in combination, to which graded doses of CsA were added to determine relative sensitivity. Proliferation, IL-2 production, and IL-2 receptor expression were assessed and the IC50 determined. Lymphocytes stimulated with Bryo exhibited a marginal proliferative response but expressed the IL-2 receptor despite the presence of CsA. Addition of anti-CD3 or anti-CD28 to Bryo-stimulated lymphocytes promoted a vigorous proliferative response. CsA effectively inhibited the proliferative response and IL-2 production induced with anti-CD3 and Bryo but did not inhibit the response of cells stimulated with anti-CD28 and Bryo. However, II-2 receptor expression in both sets of cultures were comparable due to the induction of IL-2 receptor by Bryo and was not inhibited by CsA. Costimulation of lymphocytes with anti-CD3 plus anti-CD28 resulted in a 2-3-fold enhancement of proliferation compared with lymphocytes stimulated with anti-CD3 alone. Addition of CsA to lymphocytes stimulated with anti-CD3 resulted in the dose-dependent suppression of the proliferative response and IL-2 production (IC50 = 10-25 nM) but less so for IL-2 receptor expression (IC50 = 100-150 nM). In comparison, the proliferative response and IL-2 production elicited by anti-CD3 + anti-CD28 was more resistant to the effects of CsA (IC50 = 100-200 nM). However, IL-2 receptor expression exhibited comparable sensitivity to CsA (IC50 = 100-200 nM) in the presence of anti-CD28. Combination drug:drug studies revealed that CsA and the protein kinase C inhibitor H-7 were additive for both anti-CD3 and anti-CD3 plus anti-CD28 response. On the other hand, the cGMP-dependent protein kinase inhibitor H-8 was synergistic with CsA in inhibiting the response of lymphocytes to anti-CD3 plus anti-CD28 but only additive for responses to anti-CD3. Taken together, these data suggest that CsA inhibits T cell activation at two distinct levels, leading to inhibition of IL-2 production and inhibition of IL-2 receptor expression. Activation of the CD28 pathway partially overcomes the inhibitory activity of CsA on IL-2 production and may be mediated by indirect activation of a cGMP-dependent protein kinase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The effect of the CD28 activation pathway on the immunosuppressive action of cyclosporine. 164 6

It is well established that peripheral CD8+ and CD4+ T cells display different requirements for in vitro activation by mitogenic mAb. Most CD4+ T cells can be activated by anti-CD3 or mitogenic combinations of anti-CD2. In contrast, CD8+ T cells display minimal responses to CD3 activation, and no proliferation is observed via CD2 activation. Purified peripheral blood CD8+ T cells, stringently depleted of APC, have been studied for their capacity to respond to mAb directed against CD3, CD2 and CD28, used alone or in combination. It is demonstrated that proliferation can be induced by co-stimulation of CD2 and CD28. This does not require autologous APC. CD8+ T cells can also be activated by the combination of anti-CD3 plus anti-CD28 in the presence of APC, but only minimal cell proliferation is obtained in the absence of APC. The response via CD2 plus CD28 is IL-2-dependent, as demonstrated by the ability of mAb against the IL-2 receptor to block proliferation, and is almost completely inhibited by cyclosporine A (CsA). These results suggest that the signal generated by stimulation of CD28 in combination with CD2 differs from that seen with CD28 activation combined with either PMA or CD3. Induction of IL-2 gene activation in CD8+, CD28+ peripheral T cells may therefore require additional "second signals", which are not necessary for activation of CD4+ cells. One such signal might be the interaction between CD28 and its natural ligand.
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PMID:Activation of peripheral CD8+ T lymphocytes via CD28 plus CD2: evidence for IL-2 gene transcription mediated by CD28 activation. 167 47

Human T lymphocyte proliferative response induced via CD28 molecule is analyzed. An anti CD28 MoAb, CLB-CD28/1, induces the proliferation of human peripheral blood mononuclear cells in the absence of other stimuli, indicating that CD28 molecule can directly mediate a mitogenic signal in this system. The mitogenic activity of MoAb CLB-CD28/1 on PBMC does not require MoAb interaction with monocyte Fc receptors, since F(ab')2 fragments from the MoAb are mitogenic to the same extent as whole IgG. Nevertheless, the activity depends on the presence of accessory cells, since purified T lymphocytes require addition of irradiated monocytes and interleukin 2 to proliferate when incubated with MoAb CLB-CD28/1. On the other hand, MoAb CLB-CD28/1 induces response to IL-2 in thymocytes in the absence of accessory cells. Cooperation of MoAb CLB-CD28/1 with three other MoAbs, recognizing CD3, CD5 and HLA Class I antigens, respectively, induces Tac antigen expression and IL-2 responsiveness in purified T lymphocytes. This effect is obtained without cross-linking of the MoAb. It does not rely on a physical association between CD28 and CD3, CD5 or HLA Class I molecules, as demonstrated by co-modulation experiments. These data indicate that expression of IL-2 receptor on T lymphocytes can result from interaction of multiple activation pathways and that some of them, such as those mediated by CD5 and HLA Class I antigens, previously reported to serve as modulatory circuits, can instead act as essential elements in the onset of T lymphocyte proliferation.
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PMID:Mitogenic activity of anti-CD28 MoAb CLB-CD28/1 on peripheral blood mononuclear cells and its cooperation with other anti-T cells MoAb in the activation of purified T lymphocytes. 170 Oct 62

The lymphocyte subsets in the peripheral blood were examined 3 times a week in 17 patients receiving a cadaveric renal allograft using 2-color flow cytometry and several combinations of monoclonal antibodies. Patients who experienced a rejection crisis (n = 12) had a significantly higher CD4/CD8-ratio (2.72 +/- 1.26 mean +/- SD) than patients with stable graft function (1.76 +/- 1.33, p less than 0.05). 9/12 patients showed 0-3 days prior to the rejection episode an increase of the CD4/CD8- ratio (greater than or equal to 0.5) and/or a high ratio (greater than or equal to 2.5) with a decrease following antirejection therapy. The activation markers HLA-DR and IL-2 receptor on T cells were increased only during 3/12 rejection episodes. Patients with rejections resistant to prednisone pulse therapy (n = 6) had significantly more lymphocytes/mm3 in the peripheral blood (1111.7 +/- 597.5) than successfully treated patients (n = 6, 336.7 +/- 196.0, p less than 0.02). Antirejection therapy with prednisone pulses and/or antithymocyte globuline resulted in a significant decrease of T lymphocytes (CD3+) with a selective reduction of T helper/inducer cells (CD4+). 6 months after renal transplantation the patients had a higher percentage of suppressor/cytotoxic cells (CD8+) compared to the pretransplant values (26.3 +/- 10.9% vs 17.7 +/- 6.2%, p less than 0.02) and blood donors (16.3 +/- 6.2%, p less than 0.01). Furthermore the percentage of T helper cells (CD4+/CD28-) was significantly higher and the T suppressor-inducer cells (CD4+/CD28+) were significantly lower compared to the controls. Serial flow cytometric determinations of lymphocyte subsets in renal allograft recipients may be helpful in some cases although rejection episodes could not be predicted in the individual patient.
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PMID:[The effect of rejection crises and immunosuppressive therapy on the lymphocyte subpopulations of patients after kidney transplantation]. 197 57

HIV selectively inhibited the proliferative response of clonal CD4+ T lymphocytes to alloantigen while other alloantigen-dependent responses were unperturbed. Specifically, impaired blastogenesis could be dissociated from alloantigen-specific induction of the B cell activation molecule CD23, IL-4 release, and inositol lipid hydrolysis. In addition, membrane expression of pertinent T cell receptor molecules, including CD2, CD3, and T cell antigen receptor (Ti), remained intact. Using two MHC class II-specific human CD4+ helper T cell clones, the proliferative defect was shown to be an early consequence of HIV infection, occurring within 4 d of viral inoculation and preceding increases in mature virion production. It was generalizable to three distinct methods of T cell activation, all independent of antigen-presenting cells: anti-CD3 mediated cross-linking of the CD3/Ti complex; anti-CD2 and phorbol 12-myristic 13-acetate (PMA); and anti-CD28 plus PMA. These abnormalities were not mitigated by addition of exogenous IL-2, even though expression of the IL-2 receptor (CD25) was unaltered. These studies define a selective blockade in T cell function early after HIV exposure that could serve as a model for certain in vivo manifestations of AIDS.
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PMID:Human immunodeficiency virus infection of helper T cell clones. Early proliferative defects despite intact antigen-specific recognition and interleukin 4 secretion. 247 Jul 86

CD28 is an antigen of 44 kDa which is expressed on the membrane of the majority of human T cells. The present study examines the functional effects of an anti-CD28 monoclonal antibody (mAb 9.3) on T cell activation induced with immobilized anti-CD3 mAb OKT3 or with mitogens, in the absence of accessory cells. To this end, we used blood resting T cells that were completely depleted of accessory cells (monocytes, B cells, and natural killer cells), and consequently did not respond to recombinant interleukin-2 (rIL-2), to immobilized OKT3, to PHA, or to Con A. Addition of mAb 9.3 to the cultures enhanced IL-2 receptor expression (Tac antigen) on PHA- or immobilized OKT3-stimulated T cells and induced IL-2 receptors on Con A-stimulated T cells. Moreover, addition of mAb 9.3 to cultures of T cells stimulated with PHA, Con A, or immobilized OKT3 resulted in IL-2 production. Soluble mAb 9.3 was a sufficient helper signal for T cell proliferation in response to PHA or immobilized OKT3. Crosslinking of mAb 9.3 by culture on anti-mouse IgG-coated plates enhanced the helper effect and was an essential requirement for the induction of T cell proliferation in response to Con A. No other anti-T cell mAb (anti-CD2, -CD4, -CD5, -CD7, -CD8) was found to provide a complete accessory signal for PHA or Con A stimulation of purified T cells. T cell proliferation induced by the combination of PHA and mAb 9.3 was strongly inhibited by the anti-IL-2 receptor mAb anti-Tac. In conclusion, mAb 9.3 can provide a signal bypassing monocyte requirement in T cell activation with immobilized OKT3, PHA, and Con A, resulting in an autocrine IL-2-dependent pathway of proliferation.
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PMID:The anti-T cell monoclonal antibody 9.3 (anti-CD28) provides a helper signal and bypasses the need for accessory cells in T cell activation with immobilized anti-CD3 and mitogens. 253 66

Quiescent T cells can be induced to express many genes by mitogen or antigen stimulation. The messenger RNAs of some of these genes undergo relatively rapid degradation compared to messenger RNAs from constitutively expressed genes. A T cell activation pathway that specifically regulates the stability of messenger RNAs for the lymphokines interleukin-2, interferon-gamma, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor is induced by stimulation of the CD28 surface molecule. This pathway does not directly affect the steady-state messenger RNA level, transcription, or messenger RNA half-life of other T cell activation genes, including c-myc, c-fos, IL-2 receptor, and the 4F2HC surface antigen. These data show that stimuli received at the cell surface can alter gene expression by inducing specific changes in messenger RNA degradation.
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PMID:Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway. 254 May 28

CD28 is a homodimeric glycoprotein expressed on the surface of a major subset of human T cells that has recently been identified as a member of the immunoglobulin supergene family. The binding of monoclonal antibodies to the CD28 antigen on purified T cells does not result in proliferation; however, previous studies have shown that the combination of CD28 stimulation and protein kinase C activation by phorbol myristate acetate (PMA) results in T-cell proliferation that is independent of both accessory cells and activation of the T-cell receptor-CD3 complex. In the present study, effects of stimulation by anti-CD28 on cell cycle progression and on the interleukin 2 (IL-2) and IL-2 receptor system have been investigated on primary cultures of purified peripheral-blood CD28+ T cells. There was no measurable effect on cell size or on DNA synthesis after stimulation of resting (G0) cells by CD28 alone. After 3 h of activation of T cells by PMA alone, a slight (8%) increase in cell volume occurred that did not progress to DNA synthesis. In contrast, T-cell stimulation by CD28 in combination with PMA resulted in a progressive increase in cell volume in approximately 100% of cells at 12 to 14 h after stimulation. Northern blot (RNA blot) analysis revealed that CD28 stimulation alone failed to cause expression of the alpha chain of the IL-2 receptor or of IL-2 mRNA, and in accord with previous studies, stimulation by PMA alone resulted in the accumulation of IL-2 receptor transcripts but no detectable IL-2 mRNA. In contrast, T-cell stimulation by the combination of CD28 and PMA resulted in the appearance of IL-2 transcripts and enhanced expression of IL-2 receptor mRNA. Functional studies revealed that the proliferation induced by CD28 and PMA stimulation was entirely resistant to cyclosporine, in contrast to T-cell activation induced by the CD3-T-cell receptor complex. Cyclosporine was found not to affect the accumulation of IL-2 mRNA after CD28 plus PMA stimulation, although there was no detectable IL-2 mRNA after stimulation by CD3 in the presence of the drug. Furthermore, stimulation by CD28 in combination with immobilized CD3 antibodies caused a striking enhancement of IL-2 mRNA expression that was, in part, resistant to the effects of cyclosporine. These studies indicate that the CD28 molecule synergizes with protein kinase C activation to induce IL-2 gene expression and demonstrate that stimulation by the CD28 pathway can cause vigorous T-cell proliferation even in the presence of cyclosporine and that cyclosporine does not prevent transcription of 16-2 mRNA, as has been suggested previously. Moreover, these findings suggest that a potential role for the CD28 molecule in vivo may be to augment IL-2 production after stimulation of the CD3-T-cell receptor molecular complex and thereby to amplify an antigen-specific immune response. Finally, these results provide further evidence that the CD28 molecule triggers T-cell proliferation in a manner that differs biochemically from CD3-T-cell receptor-induced proliferation.
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PMID:T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. 283 Apr 95


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