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)

In this study, we have investigated cytokine (IL-1 beta, IL-2, IL-5, IL-6, IFN-gamma, TNF-alpha) and T cell surface molecule (IL-2 receptor, CD28, CTLA-4) gene expression in two way mixed lymphocyte cultures (MLC) enhanced by concanavalin A (ConA) to assess whether this is a useful predictive method for severe graft-versus-host disease (GVHD) and graft failure in allogeneic bone marrow transplantation (allo BMT) patients. Our present study revealed increased mRNA expression of IL-2, IL-5 and IFN-gamma using this assay in patients with delayed engraftment followed by graft failure and patients who developed grade III acute GVHD. Elevated IL-2 and IFN-gamma levels in MLC medium were also observed in these patients. Concerning T cell surface molecule gene expression in our modified MLC, IL-2 receptor gene expression was not altered so much in allo BMT patients, however, CD28 and CTLA-4 gene expression were elevated in patients with graft failure and severe acute GVHD. The elevated expression of cytokines (IL-2, IL-5 and IFN-gamma) and T cell surface molecules (CD28 and CTLA-4) mRNA in our modified MLC, in patients who developed severe lethal transplantation-related complications may suggest an important role for these molecules in inducing a strong alloresponse. Therefore, the detection of increased gene expression of those molecules, in our modified MLC system, appeared to be useful for predicting transplantation-related complications in allo BMT patients. In addition, this modified MLC assay may also be useful for the selection of the most compatible related and unrelated donors.
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PMID:Transplantation-related complications predicted by cytokine gene expression in the mixed lymphocyte culture in allogeneic bone marrow transplants. 857 69

Intravenous sensitization of C57BL/6 (B6) mice with class II H-2-disparate B6-C-H-2bm12(bm12) resting B cells induced anti-bm12 CD4+ T cell tolerance as shown by hyporesponsiveness in the anti-bm12 mixed lymphocyte reaction (MLR). The present study investigated the mechanism(s) of the failure of bm12 B cells to stimulate the proliferation of B6 anti-bm12 CD4+ T cells. While stimulation in vitro to B6 splenic T cells with bm12 antigen-presenting cells (APC) induced IL-2 mRNA expression and IL-2 production, T cells stimulated with bm12 B cells expressed much less IL-2 mRNA and secreted very low but detectable levels of IL-2. Moreover, the T cells stimulated with the bm12 B cells did not proliferate and this was not corrected by the addition of rIL-2 responsiveness. Further, whereas IL-2 receptor (IL-2R) alpha chain expression was significantly induced on B6 T cells stimulated with bm12 APC; stimulation with bm12 B cells did not induce IL-2R expression over background levels. However, virgin T cells stimulated with both bm12 B cells and anti-CD28 mAb proliferated and displayed a dramatic increase in IL-2 production as well as IL-2R expression to levels commensurate with those resulting from bm12 B cells plus anti-CD28 mAb even in the presence of sufficient amounts of anti-IL-2 mAb for neutralizing produced IL-2; while levels of IL-2R were significantly lower compared to those induced in the absence of anti-IL-2 mAb, increased frequencies of IL-2R+ cells were comparable. Conversely, IL-2R was not induced by bm12 B cell stimulation in the presence of IL-2. Moreover, IL-2R expression and proliferation induced by stimulation with bm12 APC was inhibited by CTLA-4-Ig, a soluble recombinant fusion protein capable of blocking the CD28 co-stimulatory signals not only stimulate IL-2 production but also induce IL-2R expression by an IL-2-independent mechanism.
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PMID:CD28 co-stimulatory signals induce IL-2 receptor expression on antigen-stimulated virgin T cells by an IL-2-independent mechanism. 867

CTLA-4 is a CD28 homologue believed to be a negative regulator of T cell function. However, the mechanism of this downregulatory activity is not well understood. The present study was designed to examine the effect of CTLA-4 ligation on cytokine production, cell survival, and cell cycle progression. The results demonstrate that the primary effect of CTLA-4 ligation is not the induction of apoptosis. Instead, CTLA-4 signaling blocks IL-2 production, IL-2 receptor expression, and cell cycle progression of activated T cells. Moreover, the effect of CTLA-4 signaling was manifested after initial T cell activation. Inhibition of IL-2 receptor expression and cell cycle progression was more pronounced at late (72 h) time points after initial activation. The effects of anti-CTLA-4 mAbs were most apparent in the presence of optimal CD28-mediated costimulation consistent with the finding that CTLA-4 upregulation was CD28-dependent. Finally, the addition of exogenous IL-2 to the cultures restored IL-2 receptor expression and T cell proliferation. These results suggest that CTLA-4 signaling does not regulate cell survival or responsiveness to IL-2, but does inhibit CD28-dependent IL-2 production.
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PMID:CTLA-4 ligation blocks CD28-dependent T cell activation. 867 75

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.
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PMID:Altered expression of various receptors on T cells in young and old mice after mitogenic stimulation: a flow cytometric analysis. 914 64

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

Chemokines are key molecules in promoting leukocyte migration and, for some of them, T cell adhesion and activation. Lymphotactin, which is the unique known member of the C class of chemokines, is produced by and acts on T lymphocytes, but the requirement of co-stimulatory pathways such as CD28 for its expression is largely unknown. CD28 plays a dominant role in the amplification of T cell proliferation, survival and cytokine production. In this report, we demonstrate that human lymphotactin expression, at both the mRNA and protein levels, is optimally induced by CD3/TCR activation alone, whereas CD28 co-stimulation turns off this expression. This down-regulation is not attributable to secondary activation via CTLA-4, the alternative counter-receptor of B7 ligands. Only the CD4(+) and not the CD8(+) subset is directly affected by this negative regulation. Transcript destabilization can be ruled out as a mechanism by which CD28 down-regulates lymphotactin expression. However, such down-regulation can be partly induced by IL-2 and abrogated by blocking IL-2/IL-2 receptor interaction. This particular profile of lymphotactin expression is not in line with the prevailing dogma of up-regulation of cytokine gene expression by CD28 co-stimulation, and represents a new CD28-mediated regulatory mechanism for lymphotactin expression.
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PMID:CD28 co-stimulation results in down-regulation of lymphotactin expression in human CD4(+) but not CD8(+) T cells via an IL-2-dependent mechanism. 1045 58

Many lymphocyte-activation-associated molecules are observed by immunohistochemistry in psoriasis vulgaris lesional skin. Non-T cells in lesional skin also express these molecules. We quantitatively measured the number of T cells expressing cell surface activation-associated molecules (CD69, CD25, CD122, HLA-DR) and co-stimulatory molecules (CD28, CTLA-4, CD80, CD86), including a Type 2 T cell marker (CD30) and CD11b, by flow cytometry of skin and peripheral blood. T cells in single cell suspensions of psoriatic lesional-epidermis-expressed HLA-DR (86%), CD69 (59%), CD25 (55%), CD122 (44%), and CD28 (91%). Dermal T cells showed similar percentages except for CD69 (17%). CD69 was found directly in lesional skin biopsies by immunohistochemistry. Both CD4 and CD8 subsets from lesional skin contained large populations of CD25+ cells with a bias towards CD8 activation in the epidermis and towards CD4 activation in the dermis. CD86, CD80, CTLA-4, CD30 and CD11b were expressed by less than 23% of the T cell populations from both the epidermis and dermis. CD30+CD4+ cells were found two-fold over CD8+ T cells. These results show that the majority of lesional lymphocytes are persistently activated. We also found the majority of Type 2 associated markers primarily on the CD4+ epidermal T cell population. Psoriatic blood contained elevated levels of T cells expressing CD25, primarily within the CD8+ subset. Thus the majority of lesional T cells expressed the three primary activation markers, while psoriatic blood T cells were distinguished by an increase in CD25, specifically within the CTL population.
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PMID:CD69, HLA-DR and the IL-2R identify persistently activated T cells in psoriasis vulgaris lesional skin: blood and skin comparisons by flow cytometry. 1064 17

CD4(+)CD25(+) T cells in mice and rats are capable of transferring protection against organ-specific autoimmune disease and colitis and suppressing the proliferation of other T cells after polyclonal stimulation in vitro. Here we describe the existence in humans of CD4(+)CD25(+) T cells with the same in vitro characteristics. CD4(+)CD8(-)CD25(+) T cells are present in both the thymus and peripheral blood of humans ( approximately 10 % of CD4(+)CD8(-) T cells), proliferate poorly in response to mitogenic stimulation and suppress the proliferation of CD4(+)CD25(-) cells in co-culture. This suppression requires cell contact and can be overcome by the addition of exogenous IL-2. CD4(+)CD25(+) cells from thymus and blood were poor producers of IL-2 and IFN-gamma, and suppressed the levels of these cytokines produced by CD4(+)CD25(-) cells. However, CD4(+)CD25(+) PBL produced higher levels of IL-4 and similar amounts of IL-10 as CD4(+)CD25(-) cells. Regulatory CD4(+)CD25(+) T cells have an activated phenotype in the thymus with expression of CTLA-4 and CD122 (IL-2Rbeta). The fact that CD4(+)CD25(+) regulatory T cells are present with a similar frequency in the thymus of humans, rats and mice, suggests that the role of these cells in the maintenance of immunological tolerance is an evolutionarily conserved mechanism.
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PMID:Human CD4(+)CD25(+) thymocytes and peripheral T cells have immune suppressive activity in vitro. 1129 51

Thymectomy in mice on neonatal day 3 leads to the development of multiorgan autoimmune disease due to loss of a CD(+)CD25(+) T cell regulatory population in their peripheral lymphoid tissues. Here, we report the identification of a CD4(+) population of regulatory T cells in the circulation of humans expressing high levels of CD25 that exhibit in vitro characteristics identical with those of the CD4(+)CD25(+) regulatory cells isolated in mice. With TCR cross-linking, CD4(+)CD25(high) cells did not proliferate but instead totally inhibited proliferation and cytokine secretion by activated CD4(+)CD25(-) responder T cells in a contact-dependent manner. The CD4(+)CD25(high) regulatory T cells expressed high levels of CD45RO but not CD45RA, akin to the expression of CD45RB(low) on murine CD4(+)CD25(+) regulatory cells. Increasing the strength of signal by providing either costimulation with CD28 cross-linking or the addition of IL-2 to a maximal anti-CD3 stimulus resulted in a modest induction of proliferation and the loss of observable suppression in cocultures of CD4(+)CD25(high) regulatory cells and CD4(+)CD25(-) responder cells. Whereas higher ratios of CD4(+)CD25(high) T cells are required to suppress proliferation if the PD-L1 receptor is blocked, regulatory cell function is shown to persist in the absence of the PD-1/PD-L1 or CTLA-4/B7 pathway. Thus, regulatory CD4 T cells expressing high levels of the IL-2 receptor are present in humans, providing the opportunity to determine whether alterations of these populations of T cells are involved in the induction of human autoimmune disorders.
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PMID:CD4+CD25high regulatory cells in human peripheral blood. 1146 40

Specific and selective immunological unresponsiveness to donor alloantigens can be induced in vivo. We have shown previously that CD25+CD4+ T cells from mice exhibiting long-term operational tolerance to donor alloantigens can regulate rejection of allogeneic skin grafts mediated by CD45RB(high)CD4+ T cells. In this study, we wished to determine whether donor-specific regulatory cells can be generated during the induction phase of unresponsiveness, i.e., before transplantation. We provide evidence that pretreatment with anti-CD4 Ab plus a donor-specific transfusion generates donor-specific regulatory CD25+CD4+ T cells that can suppress rejection of skin grafts mediated by naive CD45RB(high)CD4+ T cells. Regulatory cells were contained only in the CD25+ fraction, as equivalent numbers of CD25-CD4+ T cells were unable to regulate rejection. This pretreatment strategy led to increased expression of CD122 by the CD25+CD4+ T cells. Blockade of both the IL-10 and CTLA-4 pathways abrogated immunoregulation mediated by CD25+ T cells, suggesting that IL-10 and CTLA-4 are required for the functional activity of this population of immunoregulatory T cells. In clinical transplantation, the generation of regulatory T cells that could provide dynamic control of rejection responses is a possible route to permanent graft survival without the need for long-term immunosuppression.
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PMID:CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses. 1180 41


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