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)

We have defined a population of CD3-, CD56+ small lymphocytes (SLs) that exhibit the same phenotype and lytic capacity as natural killer (NK) cells. NK cells characteristically express the surface markers CD16 and CD56, mediate non-major histocompatibility complex (MHC)-restricted lysis, and have been equated with CD3- large granular lymphocytes (LGLs). In the present study we extended the observation that CD3-, CD56+ SLs can mediate NK- and antibody-dependent cellular cytotoxicity activity by studying the activation signals and lytic mechanisms that might be utilized by CD3-, CD56+ SLs in comparison to CD3- CD56+ LGLs. Our results show that CD3- SLs, similar to CD3- LGLs, exhibited activated killing in response to interleukin-2 (IL-2). In addition, after IL-2 activation, the CD3- SLs exhibited morphologic changes, including increases in size and granularity, and both morphologically and phenotypically became virtually indistinguishable from CD3- LGLs. Similar to CD3- LGLs, CD3- SLs could be directly activated by IL-2 alone to secrete significant quantities of interferon-gamma (IFN-gamma) and to express IL-2 receptor (IL-2R) p55. Examination of serine esterases and pore-forming protein (PFP) demonstrated that these cells exhibited a cytoplasmic distribution of perforin, which, unlike that of CD3- LGLs, was not associated with dense cytoplasmic azurophilic granules. Serine esterase levels were similar. However, after IL-2 activation PFP was concentrated in dense cytoplasmic granules, similar or identical to the situation in CD3-, CD56+ LGLs. These CD3-, CD56+ subsets appear to represent a continuum of activated cells that might represent various states of maturation of NK cells.
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PMID:Relationship of large and small CD3- CD56+ lymphocytes mediating NK-associated activities. 138 42

In situ hybridization was used here to monitor the mRNA level of the pore-forming protein perforin in mitogen-stimulated primary peripheral blood human T cells. In situ hybridization was performed using sense and antisense ribonucleotide probes specific for this granule mediator. After IL-2 treatment, an increase in perforin mRNA could be detected by 4 h; they peaked at 12 h, and decreased after 24 h. The perforin mRNA was also induced in T cells treated with a combination of phorbol ester PMA plus lectin or OKT3 mAb. This latter induction followed slower kinetics, peaking at 48 h. For all three mitogens used, even at peak induction times less than 10% of T cells were labeled with perforin probe. Similar patterns of mRNA expression were observed for both unprimed T cells and lectin-primed T blasts. The induction response of mRNA due to IL-2 stimulation is probably mediated by the IL-2 receptor p75 chain since its mRNA was upregulated by IL-2 with a kinetics comparable to that associated with an increase of perforin mRNA. The p55 IL-2 receptor chain increased much more slowly than p75.
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PMID:Perforin gene expression in stimulated human peripheral blood T cells studied by in situ hybridization and northern blotting analysis. 142 93

Interleukin 15 (IL-15) is a novel cytokine that shares no homology with IL-2, but it requires the use of beta and gamma chains of the IL-2 receptor complex for binding and signaling. In vitro studies have shown induction of CTL and lymphokine-activated killer (LAK) cell activity in peripheral blood mononuclear cells (PBMCs) from normal donors by IL-15 against known tumor targets. The present study attempts to define the role of IL-15 in generating LAK activity from melanoma patient lymphocytes. PBMCs of patients newly diagnosed with metastatic melanoma were incubated with different doses of recombinant human IL-15 and tested against autologous tumor cells, LAK sensitive cell lines (i.e., FMEX and Daudi), as well as the natural killer-sensitive cell line K562, in a 15-h 51Cr release assay. The effect of IL-15 was found to be both time and dose dependent, with peak activity detected after 2 or 3 days of culture with 100 ng/ml of this cytokine. LAK and not CTL activity in patient PBMCs was detected by the inability of mAbs against CD4, CD8, and MHC class I to effectively block lysis of autologous tumor and FMEX melanoma cells. In addition, interaction via the CD18 adhesion molecule was shown to be critical in IL-15-induced LAK-mediated lysis of autologous tumor cells. Finally, incubation of patient PBMCs with IL-15 for 6 h resulted in the up-regulation of perforin mRNA transcription. These findings suggest that LAK activity can be generated from melanoma patient PBMCs in the presence of IL-15 to lyse autologous tumor cells in a non-MHC-restricted manner. This new cytokine may play an important role in antitumor immunity with a possible use for cancer immunotherapy.
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PMID:Interleukin 15 induction of lymphokine-activated killer cell function against autologous tumor cells in melanoma patient lymphocytes by a CD18-dependent, perforin-related mechanism. 758 40

Seven independent cell lines were derived from the fusion of migratory cells recovered from explant cultures of metrial glands to SP 2/0, a non-Ig secreting B cell myeloma. The migrating cells came from a pool of metrial glands from day 6-8 pregnant random bred CD1 mice and were assumed to be cells early in the differentiation pathway to granulated metrial gland (GMG) cells. The fused cells were cloned twice at the limiting dilution. Hybridization was confirmed by quantitation of cellular DNA using propidium iodide staining and by karyotyping. Electron microscopy revealed that each of the hybrid cell lines was composed of cells which were lymphoid in appearance, but lacked the granules found in mature GMG cells. The surface phenotype of all lines is CD45+, LGL-1-, asialo GM-1-, IgG-, IgM-, CD3- and CD25- (p55 of IL-2 receptor). Although the hybridomas lack those phenotypic markers which were used to show that GMG cells are related to the natural killer (NK) cell lineage (ie LGL-1, asialo GM-1), they do express the pan-leukocyte marker CD45 as well as the lytic protein, perforin, at levels intermediate to those of SP 2/0 cells and GMG cells. In addition, the hybridomas were observed to preferentially bind the NK target cell YAC and to be capable of lytic activity at temperatures below 30 degrees C. Because these hybridomas may represent fusion to an early progenitor cell of the NK/GMG cell lineage, their continued characterization is of merit.
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PMID:Preliminary characterization of lymphoid hybridoma cell lines derived from the pregnant mouse uterus. 780 68

Type I, insulin-dependent diabetes (IDD) in both man and animals results from a specific autoimmune destruction of the pancreatic beta cells involving both humoral and cellular immune mechanisms. The pathognomonic histologic lesion, termed insulitis, is an inflammatory and immune cell infiltrate of the pancreatic islet cells. While recent histological and flow cytometric analyses have identified the cell composition of the infiltrate, the presence of a cell population may not reflect the functional reactivities important for beta cell destruction. In the present study, we have investigated the possible functional reactivities of islet-infiltrating mononuclear cell populations by measuring increased cytokine mRNA usage. Results indicate that 1) cytokine mRNA profiles exhibited by islet-infiltrating cells of female and male NOD mice were quite similar with the exception of IL-6 expression and the marked differences in the levels of IL-2 receptor and IL-1 alpha mRNA, 2) CD4+ T lymphocytes expressed IL-4, presumably IL-5, and occasionally IL-10 mRNA but no detectable IL-2 mRNA, 3) CD8+ T lymphocytes exhibited TNF-beta, perforin and high levels of IFN-gamma, and 4) IL-7 was expressed in the islet at very high levels. These findings, together with our earlier flow cytometric analyses of the islet-infiltrating cells, have permitted construction of a detailed model for the natural history of autoimmune diabetes. Interestingly, this model, based on a TH2- and not a TH1-mediated scheme, questions the more popular concepts currently thought to form the bases of the autoimmune reactions underlying IDD.
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PMID:Insulin-dependent diabetes in the NOD mouse model. II. Beta cell destruction in autoimmune diabetes is a TH2 and not a TH1 mediated event. 810 89

Experimental autoimmune encephalomyelitis (EAE) in rats is typically a brief and monophasic disease with sparse demyelination. However, inbred DA rats develop a demyelinating, prolonged and relapsing encephalomyelitis after immunization with rat spinal cord in incomplete Freund's adjuvant. This model enables studies of mechanisms related to chronicity and demyelination, two hallmarks of multiple sclerosis (MS). Here we have investigated, in situ, the dynamics of cytokine mRNA expression in the central nervous system (CNS) and peripheral lymphoid organs (lymph node cells and splenocytes) of diseased DA rats. We demonstrate that peripheral lymphoid cells stimulated in vitro with encephalitogenic peptides 69-87 and 87-101 of myelin basic protein responded with high mRNA expression for proinflammatory cytokines; interferon-gamma, interleukin-12 (IL-12), tumour necrosis factors alpha and beta, IL-1 beta and cytolysin. A high expression of mRNA for these proinflammatory cytokines was also observed in the CNS where it was accompanied by classical signs of inflammation such as expression of major histocompatibility complex class I and II, CD4, CD8 and IL-2 receptor. The expression of mRNA for proinflammatory cytokines was remarkably long-lasting in DA rats as compared to LEW rats which display a brief and monophasic EAE. Furthermore, mRNAs for putative immunodownmodulatory cytokines, i.e. transforming growth factor-beta (TGF-beta), IL-10 and IL-4 were almost absent in DA rats, in both the CNS and in vitro stimulated peripheral lymphoid cells, while their levels were elevated in the CNS of LEW rats during the recovery phase. We conclude that the MS-like prolonged and relapsing EAE in DA rats is associated with a prolonged production of proinflammatory cytokines and/or low or absent production of immunodownmodulatory cytokines.
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PMID:Cytokines in relapsing experimental autoimmune encephalomyelitis in DA rats: persistent mRNA expression of proinflammatory cytokines and absent expression of interleukin-10 and transforming growth factor-beta. 882 81

The regulation of human natural killer (NK) cell activation is under the control of a network of regulatory signals provided by cytokines. In the present study, we investigated the functional interaction between interleukin (IL)-4 and two monocyte/macrophage-derived cytokines, IL-12 and IL-15, during the process of NK stimulation. Using freshly isolated human NK cells, we have demonstrated that IL-4 negatively regulates lymphokine-activated killer (LAK) activity induced by IL-15 against the NK-resistant Daudi target cells. In contrast, IL-4 had no effect on IL-12-stimulated LAK generation. The differential effect of IL-4 on NK cell activation by IL-12 and IL-15 correlates with its ability to increase or to down-regulate the level of tumor necrosis factor-alpha and interferon-gamma release by NK cells, respectively. In contrast, endogenous transforming growth factor-beta 1 does not appear to be involved in the IL-4 regulatory pathway. Furthermore, while IL-4 was found to decrease the basal expression of the IL-2 receptor beta subunit utilized by IL-15, it had no effect on the expression of the beta 1 chain of the IL-12 receptor compared to untreated cells. Northern blot analysis indicated that the IL-4 regulatory effect on NK lytic function was associated with its capacity to down-regulate granzyme B and perforin gene transcription in response to IL-15 and its failure to affect the expression of both gene's in response to IL-12. Together, these data suggest the existence of a distinct cross-talk between IL-4 and IL-15 or IL-12 signaling pathways during the regulation of human non-major histocompatibility complex-restricted cytotoxicity.
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PMID:Differential regulation of interleukin-12- and interleukin-15-induced natural killer cell activation by interleukin-4. 892 63

CD56 expression has been reported previously in some non-Hodgkin's lymphoma (NHL) characterization. They principally involve the nasopharynx, are related to Epstein-Barr virus (EBV), and may be classified as either T- or non-T-natural killer (NK) cells according to CD3/T-cell receptor (TCR) status at the genomic or protein level. The present study reports three cases of non-nasal NK-NHL with the following characteristics: an agressive clinical behavior, heterogenous morphological data evoking pleomorphic T-cell malignant lymphoma, a non-T-NK phenotype using flow cytometry, and immunochemistry. The three cases were CD56+ without membrane expression of specific T markers (CD3, CD5, and TCR). Heterogenous results were observed concerning different antigens: CD2, CD4, CD8, CD16, CD94, CD122, TiA1, perforin, and granzyme B. There was no evidence of detectable clonal TCR gene rearrangement with polymerase chain reaction. No NK activity was detected in the two tested cases, and no relation was found with EBV. Multidrug resistance investigations suggest that agressive clinical findings could be related to MDR1 gene expression as confirmed by MDR1 mRNA detection, MDR1 gene product (Pgp) expression, and a functional multidrug resistance study using rhodamine efflux by flow-cytometry.
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PMID:CD3- CD56+ non-Hodgkin's lymphomas with an aggressive behavior related to multidrug resistance. 910 17

To analyze the early development of T cell precursors in the absence of TCR gene rearrangement, recombinase-activating gene-deficient (RAG-2 -/-) thymocytes were compared with thymocytes from SCID mice on the C.B-17 (BALB) and B6 genetic backgrounds. RAG-2 -/- thymocytes accumulate as quiescent cells with a heat-stable Ag (HSA)-positive CD25+ CD44- c-kit(low) phenotype, resembling normal cells just before selection for functional TCR beta-chain expression. CD44 and c-kit progressively down-regulate in the HSA+ subset, providing a background-independent and TCR-independent developmental clock. On this basis, compared with RAG-2 -/- thymocytes, SCID thymocytes 1) arrest at more heterogeneous, and generally earlier, stages; 2) accumulate to lower overall cell numbers; and 3) maintain higher populations of cycling and activated G1 cells, showing both increased responsiveness and increased cell death. B6-SCID thymocytes appear to die particularly early. Low levels of Fas were observed on "advanced" HSA+ SCID thymocytes but not on any RAG-2 -/- thymocytes, suggesting a potential difference in activation state or mechanism of death. In both RAG-2 -/- and SCID thymocytes, there are also two discrete subsets of HSA(low) CD25- CD44+ c-kit+ cells: a Sca-1+ CD44++ CD122- NK1.1- putative progenitor subset and an NK-like Sca-1- CD44+(+) CD122+ NK1.1+ subset. The absolute cell numbers in these HSA(low) subsets and the extent of NK cell differentiation, measured by perforin expression, are nearly constant in all the mutant strains analyzed, in contrast to the HSA+ CD25+ population, which was expanded in the RAG-2 -/-. Thus, the SCID thymocytes appear to undergo a normal generation but a premature death as compared with the RAG-2 -/- thymocytes.
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PMID:Different developmental arrest points in RAG-2 -/- and SCID thymocytes on two genetic backgrounds: developmental choices and cell death mechanisms before TCR gene rearrangement. 912 63

CD56 (NCAM)-positive lymphoma frequently involves the skin and nasal area. This study shows it is likely that the clinicopathologic features of this lymphoma are distinctive to each of the primarily involved sites. Sixteen cutaneous and 11 nasal cases of CD56-positive lymphoma were examined. In 10 cutaneous cases, the lesions consisted of pleomorphic large-cell lymphoma that expressed CD3epsilon (CD3), CD2 (LFA2), CD4, CD122 (IL-2B receptor), TIA1, perforin, and granzyme B and displayed angiocentric/angiodestructive features. Lobular panniculitis was found in 8 of these cases, and 6 cases showed other organ involvement. The remaining 6 cutaneous cases consisted mostly of CD3epsilon- and CD4-positive, CD2-, CD122-, and TIA1-negative large blastic lymphoma, having less angiodestruction and panniculitis. Bone marrow invasion and leukemic changes were found in 4 of these cases during the clinical course. All 11 nasal cases showed pleomorphic small and medium-size lymphoma cells with angiodestructive features and were positive for CD3epsilon, CD2, CD122, TIA1, perforin, and granzyme B. CD4-positive lymphoma was found in 4 of these cases. Only 3 nasal cases showed other organ involvement. Genotypically, 2 of the 4 cases examined in the first cutaneous group, 3 of the 4 cases examined in the second cutaneous group, and only 1 of the 11 nasal cases showed rearrangement of the TcRCbeta gene by the Southern blot method. Only 2 cutaneous cases with panniculitis and all 11 nasal cases showed a positive nuclear signal for EBV-encoded RNA (EBERs) by in situ hybridization. Thus, two types of cutaneous CD56-positive lymphoma were found, each having a unique cell characteristic, genotype, and EBV infection pattern that differed from that of nasal-type lymphoma.
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PMID:Cases of cutaneous and nasal CD56 (NCAM)-positive lymphoma in Japan have differences in immunohistology, genotype, and etiology. 1049 36


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