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Query: UNIPROT:P06889 (Mol)
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The expression of the human IL-2 recombinant gene in E. coli cells was studied. The processes which take place during thermo-induced expression and effect the state of the product were investigated. Experimental data on the membrane localisation of IL-2, the formation of aggregates (inclusion bodies) and polymers were obtained. It was determined that temperature significantly influence the kinetics of the processes of intracellular IL-2 production and IL-2 stability. It is supposed that the cell membrane state plays a determining role in these processes via temperature mediation. Thus, the formation of inclusion bodies described for a number of E. coli recombinant strains is probably stipulated not only by recombinant polypeptides properties, but also by cellular interactions.
Mol Biol (Mosk)
PMID:[A study of the intracellular fate of recombinant human interleukin 2 in Escherichia coli]. 268 47

Several monoclonal antibodies directed against a number of T cell surface molecules are used to elucidate the role of these molecules (cell surface molecules) in T cell activation. The activation of T cells via these molecules are both antigen-dependent (CD3/TcR complex) and antigen-independent. Irrespective of their antigen dependency, these monoclonal antibodies activate T cells by a classical signal transduction pathway, in which the binding of monoclonal antibodies to their cell surface receptors leads to activation of phospholipase C resulting in the depolarization of plasma membrane, hydrolysis of IP2 and IP3 and DAG, the 'second messengers'. IP3 leads to mobilization of intracellular calcium to contribute to an increase in [Ca++]i, whereas DAG causes activation and translocation of PKC and an increasing apparent affinity for Ca++. The role of IP4 in the mobilization of intracellular calcium is emerging. In addition, influx of extracellular calcium also contributes to increase in [Ca++]i. The increase in [Ca++]i following activation via some T cell surface antigen is predominantly due to intracellular mobilization of Ca++ (e.g. CD3/TcR complex), whereas activation via other T cell surface antigen, the increase in [Ca++]i is almost entirely due to an influx of extracellular calcium (e.g. CD5 antigen). All these molecules activate autocrine system of T cell growth, namely IL-2 production, IL-2 receptor expression and T cell proliferation.
Mol Cell Biochem
PMID:Mechanisms of transmembrane signalling in human T cell activation. 269 33

B cells can be activated by T-independent antigens or mitogens such as lipopolysaccharide (LPS) which will induce proliferation and differentiation of the B cells into Ig-secreting cells, without the intervention of T cells. The precise mechanism of T-independent proliferation and differentiation of B cells is still unclear. It is possible however that antigen-stimulated B cells may produce some factors which play a role in T-independent B-cell responses. In addition, since it has now been established that B cells can function as antigen-presenting cells, it is possible that they too secrete a molecule which is involved in the activation of T cells, analogous to IL-1 production by antigen-presenting macrophages. A number of human B-cell lines, as well as human normal B cells activated appropriately, have been shown to produce various cytokines, and similar studies are now being undertaken in the mouse. In the present study, six cloned murine B-cell lymphomas of different origin were analyzed for the presence of mRNA encoding a number of lymphokines by hybridization of specific cDNA probes to poly-A RNA, followed by the sensitive S1 nuclease digestion technique. The lymphokines included (IL-) 1, 2, 3, 4, 5, and neuroleukin. Whereas none of the lines expressed detectable levels of IL-2, IL-3, or IL-5 mRNA, all the lines expressed high levels of neuroleukin mRNA. Three of the lymphomas (CH12, CH31, and NBL) expressed low levels of IL-1 mRNA. The most striking finding was that one lymphoma, CH12, constitutively expressed IL-4 mRNA. This mRNA appeared to be functional, as IL-4 activity measured by the HT-2 T cell proliferation assay could be detected in supernatants collected from CH12 cells. The growth-inducing activity of CH12 supernatant on HT-2 cells could be completely blocked by an anti-IL-4 monoclonal (11B11), but not by an anti-IL-2 antibody (S4B6), consistent with our observations that CH12 cells produce IL-4 but not IL-2. CH12 cells were also found to express high affinity receptors for IL-4. Proliferation of CH12 cells was not affected by the addition of exogenous IL-4. Addition of anti-IL-4 antibodies to CH12 cells in culture caused a slight but reproducible increase in their proliferation at low cell numbers, which is probably not highly significant. These findings open the possibilities that murine B lymphocytes are capable of lymphokine production or alternatively that aberrant lymphokine production underlies B-lymphocyte transformation.
J Mol Cell Immunol 1989
PMID:Constitutive production of lymphokines by cloned murine B-cell lymphomas--CH12 B lymphoma produces interleukin-4. 278 29

Activation of T cells by an antigen, a mitogen, or a combination of a phorbol ester (12-O-tetradecanoylphorbol-13-acetate [TPA]) and a calcium ionophore (A23187) leads to induction of a set of lymphokine genes. Treatment of human T-cell leukemia line Jurkat by a mitogen or p40x, a transactivator protein encoded by human T-cell leukemia virus type I, activates many transfected lymphokine genes in a transient transfection assay. To study the mechanism of lymphokine gene induction, we examined the effects of mitogen stimulation and p40x on the gene for the mouse granulocyte-macrophage colony-stimulating factor (GM-CSF) in Jurkat cells. Deletion and mutation analyses showed that the 5'-flanking region of the gene for the GM-CSF is composed of two types of regulatory elements. One sequence, located at positions -95 to -73, determines response to stimulation by either TPA-A23187 or p40x. This region contains conserved lymphokine element 2, which appears in the gene for interleukin 3 (IL-3) and is followed by a GC-rich stretch. This GC-rich stretch alone specifies inducible response to p40x but not to TPA-A23187. Another sequence, located at positions -113 to -96 upstream of a TATA-like sequence, mediates inducible response to p40x but not to TPA-A23187. This sequence includes conserved lymphokine element 1, which appears in several lymphokine-cytokine genes, such as those for IL-3, G-CSF, and IL-2. We previously showed that the simian virus 40 early region promoter was also induced by a mitogen or p40x in Jurkat cells. Deletion analysis showed that the minimum region require for stimulation by both signals are identical. These results, which indicate that p40(x) stimulates transcription of the gene for the GM-CSF or the simian virus 40 early region promoter through the same DNA element or an overlapping DNA element required for induction by a mitogen, lend further support to the notion that p40(x) can exert its function by activating a component(s) of the T-cell signal transduction pathway which is activated by an antigen or a mitogen.
Mol Cell Biol 1988 Dec
PMID:T-cell activation signals and human T-cell leukemia virus type I-encoded p40x protein activate the mouse granulocyte-macrophage colony-stimulating factor gene through a common DNA element. 285 2

The murine T-lymphoma cell line LBRM-33 is known to require synergistic signals delivered through the antigen receptor (Ti-CD3) complex, together with interleukin 1 (IL-1), for activation of IL-2 gene expression and IL-2 production. Although 12-O-tetradecanoylphorbol-13-acetate (TPA) was capable of replacing IL-1 as an activating stimulus under certain conditions, biologic studies indicated that TPA failed to synergize with Ti-CD3-dependent stimuli under conditions in which IL-1 was clearly active. Acute exposure to TPA and other active phorbol esters resulted in a concentration-dependent inhibition of the increases in phosphoinositide hydrolysis and intracellular free Ca2+ concentration stimulated by phytohemagglutinin or anti-Ti antibodies. TPA treatment induced no direct alteration of phospholipase C enzymatic activities in LBRM-33 cells. In contrast, both Ti-CD3 cross-linkage and TPA rapidly stimulated the phosphorylation of identical CD3 complex polypeptides, presumably via activation of protein kinase C. Exposure of LBRM-33 cells to TPA resulted in a time-dependent, partial down-regulation of surface Ti-CD3 expression. Thus, TPA treatment inhibited the responsiveness of LBRM-33 cells to Ti-CD3-dependent stimuli by inducing an early desensitization of Ti-CD3 receptors, followed by a decrease in membrane receptor expression. These studies indicate that phorbol esters deliver bidirectional signals that both inhibit Ti-CD3-dependent phosphoinositide hydrolysis and augment IL-2 production in LBRM-33 cells.
Mol Cell Biol 1988 Dec
PMID:Inhibition of T-cell antigen receptor-mediated transmembrane signaling by protein kinase C activation. 297 23

Recent advances in the biochemical and genetic analysis of soluble immunoregulatory molecules (TsF) have been achieved via the establishment of cloned TsF-producing T cell hybridomas. However, studies on in vivo regulation of immune responses have been hampered by the lack of clonal populations of nontransformed suppressor T cells (Ts). Nonhybridoma Ts clones would allow cellular dissection of complex Ts circuits and precise analyses of Ts effector mechanisms. Our laboratory has recently demonstrated that poly(Glu60Ala30Tyr10) (GAT)-specific unresponsiveness is induced in adult responder mice tolerized via the intravenous injection of GAT-coupled syngeneic spleen cells (GAT-SP). This unresponsiveness is mediated by two antigen-specific mechanisms--nontransferable clone inhibition and induction of transferable Ts which regulate both humoral and T cell-mediated delayed-type hypersensitivity (DTH) responses. We have thus applied methodology used for the production and maintenance of antigen-specific T helper (Th) clones in an attempt to establish and characterize Ts clones mediating GAT-specific in vivo suppressive activity. Therefore, spleen cells from GAT-SP tolerant responder mice were maintained in continuous culture with soluble GAT, 10% concanavalin A-conditioned medium (IL-2), and irradiated syngeneic antigen presenting cells (APC). A stable, long-term Ts cell line (J372) was isolated by this procedure. This line and one of its clones (J372.2) suppressed the afferent (induction), but not efferent (elicitation) phase of GAT-specific DTH. In contrast, the J372.2 Ts clone had no inhibitory effect on the development of specific T cell proliferative responses. Intravenous injection of small numbers (2-5 x 10(6)) of J372.2 Ts cells resulted in significant suppression of DTH responses in GAT-primed, but not in ovalbumin- or methylated bovine serum albumin-primed recipients, demonstrating the antigen-specificity of the suppression. Intravenous injection of a GAT-specific Th clone (JTL-E1) or of a DNP-specific Th line (JTL-DNP) had no suppressive effects on GAT-specific responses suggesting that J372.2-mediated unresponsiveness is the result of active suppression, and not the result of nonspecific inhibitory effects of activated T cells. More importantly, normal GAT-specific DTH responses in recipients of the JTL-E1 Th clone (maintained in the same GAT concentration as J372.2) indicated that J372.2-mediated suppression was not due to induction of nontransferable tolerance by surface-associated GAT.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Cell Immunol 1985
PMID:Immunoregulatory pathways in adult responder mice. III. Establishment of a GAT-specific suppressor T cell clone from GAT-tolerant responders which afferently regulates DTH responses. 297 21

Human T-cell leukemia virus (HTLV)-infected cell lines derived from adult T-cell leukemia (ATL) express constitutively the receptor for Interleukin-2 (IL-2-R) and the associated antigen (Tac antigen). In contrast, the same antigen is transiently expressed by normal T-cells only after immune stimulation. Recently, it was reported that the constitutively expressed Tac antigen on ATL cells and cell lines was not down-regulated or modulated by anti-Tac antibody. Since the antigen was modulated on normal mitogen- or alloantigen-stimulated T-cells, we postulated that the regulation of IL-2-R may be abnormal on ATL cells; the synthesis of IL-2-R is continuously stimulated in these cells. A unique HTLV/ATLV(-) cell line (YT) derived from a child with acute lymphoblastic leukemia was found to express low levels of Tac antigen that could be enhanced by various stimuli, including conditioned medium (CM) derived from normal lymphocytes, but not by lectins (PHA, Con A). Of particular interest, the exposure of YT cells to CM from ATL cell lines with helper phenotype revealed the presence of factor(s) (ATL-derived factor, ADF) that augmented the synthesis and expression of IL-2-R/Tac antigen on YT cells and promoted YT cell growth. CM from HTLV(-) leukemia cell lines lacked both IL-2-R augmenting activity and a growth promoting activity. Immunoaffinity-purified IL-2 and recombinant gamma interferon also lacked IL-2-R augmenting activity. Moreover, the physicochemical analysis with Fast protein liquid chromatography (FPLC) revealed that ADF was quite different in pI point from the IL-2-R augmenting activity in CM from normal lymphocytes. These results suggested that ADF is a unique product of HTLV(+) cells. The possible relationship between ADF production, HTLV infection, and the abnormal expression of IL-2-R is suggested, and these abnormalities may be advantageous for the leukemogenesis and abnormal growth of ATL.
J Mol Cell Immunol 1985
PMID:Adult T leukemia cells produce a lymphokine that augments interleukin 2 receptor expression. 297 23

Sharing of "idiotypes" by T and B cells with similar nominal specificities has been extensively reported in functional assays. The recent molecular characterization of T cell receptors has led to the suggestion that such idiotypic mimicries could result from "network" selection of available T cell repertoires. Alternatively, the validity of the conclusions taken from those functional assays could be questioned. We have now used an experimental system where recurrent expression of antibody idiotypes by T helper cells requires "learning" from the B cell/antibody compartment, and show here that the idiotypic determinants in question are indeed associated with T cell receptor molecules. A monoclonal antibody (F6(51)) directed to an idiotope of the TNP-binding BALB/c myeloma protein MOPC460 specifically inhibits antigen-dependent proliferation and helper activity of BALB/c anti-TNP-BALB/c helper T cells. The anti-idiotypic antibodies also induce IL-2 production by these helper cells and precipitate a surface molecule with characteristics of T cell receptor. We conclude that, in this particular system, T cell receptors and antibodies of similar nominal specificities share idiotypic determinants.
J Mol Cell Immunol 1986
PMID:Functional and biochemical evidence for the recognition of T cell receptors by monoclonal antibodies to an immunoglobulin idiotype. 297 35

Idiotypic cross-reactivities between T and B cell receptors have been taken in the past to suggest VH-gene expression by both types of lymphocytes. More recently, after the molecular characterization of TcR, those observations were reinterpreted to indicate idiotypic network regulation, operating to select cross-reactive idiotypes in both B and T cell compartments. In support of these views, it has been shown that T cell expression of idiotypes is controlled by IgH-linked genes and markedly altered in B cell-deprived mice, and that T cells "learn" idiotype expression from the B cell compartment in the first few weeks of life. In most of these studies, aleatory idiotype cross-reactivities have not been sufficiently considered. Given the large diversity of antibodies and TcR, and the degeneracy of antibody-ligand interactions, it could be expected that a (monoclonal) anti-idiotypic reagent prepared against an antibody idiotope will always "cross-react" with some TcR variable regions. If these will be "major" T cell clonotypes, situations of idiotype sharing by B and T cells can be found which indicate neither VH-gene expression by T cells nor idiotypic network regulation. We report here one example of such aleatory expression of antibody idiotypes by T lymphocytes. A monoclonal anti-idiotypic antibody directed to anti-TNP antibodies of BALB/c mice specifically inhibits the growth and effector activity of C57BL/6 anti-NP-self helper T cells, while failing to interact with either BALB/c anti-NP-self or C57BL/6 anti-TNP-self helper cells. The clonotypic nature of these interactions could also be demonstrated by the specific induction of IL-2 production in the appropriate helper T cells by the anti-idiotypic antibody.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Immunol 1987
PMID:Sporadic idiotypic cross-reactivities between antibodies and T helper cells: one example of aleatory expression of T cell idiotypes. 297 37

A bovine papilloma virus-derived vector was used to direct the high level expression in mouse C127 cells of three different cDNAs encoding the human interleukin-2 receptor. These were: the previously described cDNA clone isolated from the T-cell lymphoma, HUT-102; a cDNA clone isolated from mitogen-activated, normal peripheral blood T cells; and an altered version of the HUT-102 receptor in which Ser247, believed to be the site of protein kinase C-mediated phosphorylation, has been changed to an Ala residue. Fluorescence-activated cell-sorting using a monoclonal antibody directed against the human IL-2 receptor was used to derive stable lines of C127 cells expressing from 2-6 X 10(6) IL-2 binding sites per cell. However, all of these receptors bound IL-2 with low affinity.
Mol Immunol 1986 Sep
PMID:High level stable expression of human interleukin-2 receptors in mouse cells generates only low affinity interleukin-2 binding sites. 309 20


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