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A Schimpl

Publications and source records attributed to A Schimpl.

At least 19 recordsLinked to original sources
PubMed1992

Regulation of immunoglobulin gene expression in normal lymphocytes. II. Mechanisms of down-regulation of immunoglobulin secretion after engagement of the B cell antigen receptor.

When B cells are stimulated with lipopolysaccharide (LPS) they start to proliferate and mature into immunoglobulin (Ig)-secreting cells. Co-stimulation with F(ab')2 fragments of antibodies directed against the B cell antigen receptor leads to an inhibition of Ig secretion but not of proliferation. This effect can be mimicked by phorbol esters alone or by a combination of phorbol esters and the Ca2+ ionophore ionomycin, which activate protein kinase C. Here we report that co-stimulation with phorbol esters and ionomycin differentially affects a group of genes normally up-regulated during the course of LPS-dependent B cell activation. Thus, the mRNA coding for the membrane-bound form of IgM and the interleukin 2 receptor (55-kDa protein) continue to be expressed at the levels typical of LPS-stimulated cells, while the mRNA coding for the secreted form of IgM (mu S) and for the J chain are reduced. The loss of mu S mRNA is attributable to an altered processing behavior with respect to the mu precursor and/or a decreased stability of the mRNA itself.

Animals↗
PubMed1992

Mechanism of MHC class I downregulation in HIV infected cells.

HIV infection of CD4+ peripheral blood lymphocytes leads to a loss of MHC class I molecules on the surface of the infected cells as detectable by monoclonal antibody staining and flow cytometry. Incubation of the infected cells at 26 degrees C or treatment at 37 degrees C with peptides leads to upregulation of MHC class I to levels equal to those found on uninfected cells cultured under the same conditions. The data suggest that, after HIV infection, the mechanisms responsible for peptide generation, peptide transport and thus stable association between peptides and MHC class I molecules are severely affected.

CD4-Positive T-Lymphocytes↗
PubMed1992

Quantitative and qualitative differences in IL-2 and IL-4 expression in primary and secondary T cell stimulation.

Lymphocytes were concanavalin A (Con A) primed and the signal was withdrawn 4-48 h post-stimulation by alpha-methyl-D-mannopyranoside (alpha MM) treatment. Upon restimulation IL-2 and IL-4 RNA expression was found to be greatly enhanced. Re-expression of lymphokine RNA was dependent on signals delivered by Con A, anti-CD3 antibodies or phorbolester plus ionomycin, and could not be achieved by either IL-2, phorbolester or ionomycin alone. Increased IL-2 re-expression was only possible when alpha MM was added early after primary stimulation, while the ability for enhanced IL-4 RNA re-expression persisted. IL-2 and IL-4 RNA re-expression was characterized by increases in steady state precursor RNA levels and thus, presumably, increased rates of transcription. However, the high accumulation of IL-2 RNA observed upon restimulation was also due to greatly increased RNA stability (greater than 4 h versus 30 min after primary stimulation). Thus, secondary expression of IL-4 RNA is persistent and mostly due to quantitative changes in transcription, whereas enhanced re-expression of IL-2 RNA also results from altered post-transcriptional regulation. This phenotype, however, is only short lived.

Animals↗
PubMed1991

Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting.

Interleukin-2 (IL-2) is a lymphocytotropic hormone which is thought to have a key role in the immune response of mammalian cells. It is produced by a subpopulation of activated T-lymphocytes and acts in vitro as the principal auto- and paracrine T-cell growth factor (for reviews see refs 1-3). IL-2 is, however, not the sole T-cell growth factor, nor does it act exclusively on T cells, also promoting growth of NK cells and differentiation of B cells. A role for IL-2 in T-cell development has been postulated but remains controversial. Here we test the requirement for IL-2 in vivo using IL-2-deficient mice generated by targeted recombination. We find that mice homozygous for the IL-2 gene mutation are normal with regard to thymocyte and peripheral T-cell subset composition, but that a dysregulation of the immune system is manifested by reduced polyclonal in vitro T-cell responses and by dramatic changes in the isotype levels of serum immunoglobulins.

Animals↗
PubMed1991

Regulation of lymphokine expression in T cell activation. I. Rapid loss of interleukin-specific RNA after removal of the stimulating signal.

Resting T lymphocytes can be induced to express a variety of lymphokines after antigenic or mitogenic stimulation. Expression is regulated both at the transcriptional level, through induction of T cell-specific DNA-binding proteins, and at the post-transcriptional level through alteration of precursors or mRNA stability. To investigate whether lymphokine expression follows a preprogrammed course after activation of T cells or whether it is dependent on the continued monitoring of activating signals, we followed the fate of interleukin (IL) 2, IL 4 and IL 2 receptor mRNA after removal of the stimulating signal concanavalin (Con A) by alpha-methylmannoside (alpha MM). IL 2 and IL 4 needed continued stimulation of the cells for RNA expression, as shown by the rapid disappearance of IL 2 and IL 4 mRNA after addition of alpha MM to stimulated cells, while IL 2 receptor mRNA which is also induced after Con A stimulation was minimally influenced. In the case of both IL no new mature mRNA was generated after removal of the stimulating signal. The T1/2 of IL 2 mRNA remained unchanged after alpha MM treatment as compared to actinomycin D treatment, while IL 4 mRNA became labilized after withdrawal of the signal.

Animals↗
PubMed1990

Regulation of Ig gene expression in normal lymphocytes. I. The half-life of secreted mu chain mRNA differs from that of membrane mu chain mRNA in resting and activated B cells.

Resting and activated B lymphocytes were used to study the stability of mu-specific precursor and mature mRNA. Resting cells which predominantly process the mu precursor towards micron do so rather slowly as reflected in a precursor half-life (T1/2) of 1-2 h. The small amount of secreted mu chain mRNA is fairly stable (T1/2 approximately 8 h) compared to membrane mu chain (T1/2 approximately 4 h). After activation the precursor processing is very fast (T1/2 approximately 10 min) and the stability of mu2, which now predominates, increases (T1/2 approximately 16 h) while the half-life of micron remains at about 4 h. The data indicate that normal B cells regulate mu-specific mRNA stability differently from tumor cells of the B cell lineage.

Animals↗
PubMed1989

Downregulation of HLA class I antigens in HIV-1-infected cells.

By means of indirect immunofluorescence analysis we investigated the effect of HIV-1 infection on HLA class I surface antigens. We report here that in CD4+ HeLa cells, in H9 cells, and in peripheral T lymphocytes HLA class I antigens are downregulated following infection with HIV-1. The downregulation is effected at a posttranscriptional level since the amounts of HLA class I specific mRNA are similar in infected and uninfected cells. This phenomenon is not only correlated with the state of infection, that is, the presence of P24 of HIV-1 in the cells, but also depends on the time of infection. Upon HLA class I downregulation by HIV infection, the specific lysis of peripheral blood cells by allogeneic CTL is reduced.

CD4-Positive T-Lymphocytes↗
PubMed1989

Lymphokines.

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Animals↗
PubMed1987

Kinetics of cellular oncogene expression in mouse lymphocytes. II. Regulation of c-fos and c-myc gene expression.

Newly isolated lymphocytes from mouse spleens express the c-fos oncogene even in the absence of mitogen with maximal mRNA levels 60 min post preparation of single cell suspension, whereas c-myc mRNA levels increase only after mitogenic stimulation with maximal mRNA levels 6 h post stimulation. The half-lives of c-fos mRNA are generally very short; they increase from 14 min (after 30 min of culture) to 70 min (after 2 h of culture). The half-lives of c-myc mRNA decrease from 50 min (at 2 and 6 h post stimulation with concanavalin A) to 12 min (at 48 h post stimulation). The c-fos gene transcription is already turned on in time-0 lymphocytes 10 min after disruption of the organ structure of the spleens and is down-regulated after 2 h and later. In nuclear run-on experiments with nonstimulated lymphocytes there is already significant transcription of the first exon of c-myc, but almost no elongation of the transcript to exon 2 and 3. In concanavalin A-treated lymphocytes elongation is stimulated about 5-fold within 6 h and returns to background levels at 48 h post stimulation. The nuclear run-on analyses of nonactivated lymphocytes showed a signal for RNA complementary to c-myc mRNA detected with a probe specific for the exon 1/intron 1 boundary of c-myc, which disappeared with increasing time of concanavalin A stimulation. This anti-sense transcription may play a role in regulating the elongation of c-myc transcripts.

Animals↗
PubMed1987

Regulation of IL 2 expression in mitogen-activated murine T lymphocytes.

In mitogen-stimulated mouse spleen cells, the IL 2 gene is only transiently expressed with maximal mRNA steady state levels between 6-14 h post stimulation with Concanavalin A (Con A). This is also reflected by the kinetics of IL 2 release into culture supernatants. Con A-stimulated L3T4+ and Lyt2+ T cell subpopulations express the IL 2 gene and produce IL 2 similarly. The half-life of IL 2 mRNA is only 30 min, but can be prolonged significantly by cycloheximide. At later post stimulation times IL 2 gene transcription is reduced, as indicated by the reduced effect of cycloheximide. IL 2 gene expression is not influenced by added IL 2 or IFN-gamma.

Animals↗
PubMed1987

Transcriptional control of mu- and kappa-gene expression in resting and bacterial lipopolysaccharide-activated normal B cells.

When murine resting B cells are polyclonally stimulated by bacterial lipopolysaccharide (LPS) in vitro for a short period of 4 days, they are activated to DNA synthesis and cell division, and they also differentiate to immunoglobulin (Ig)-secreting plasma cells. These two events are accompanied with several qualitative changes at the Ig mRNA level: the disappearance of delta mRNA after stimulation, the switch from membrane to secretory form of mu-mRNA, and the late appearance of IgM joining chain (J-chain) mRNA. There is also a quantitative increase of Ig-gene expression at the level of: Ig gene transcription, mu-, kappa- and J-chain mRNA accumulation, and Ig translation and secretion. A comparison of Ig transcription rates before and in the course of LPS stimulation, as determined by in vitro transcriptional run-on assays, has shown that there is a large increase of the RNA polymerase density on both mu- and kappa-loci (30-60-fold), which is quantitatively comparable with the accumulation of both mu- and kappa-mRNAs at the steady state mRNA level. These data therefore suggest that former results obtained with tumor cells regarding post-transcriptional control of Ig gene expression do not reflect the physiological behavior of normal B cells with respect to the molecular events of B cell triggering. We also propose that additional molecular events such as RNA processing and the transcriptional activation of J-chain gene might be essential for controlling the maximal transcriptional rate across the Ig loci.

Animals↗
PubMed1987

Tumor necrosis factor amplifies measles virus-mediated Ia induction on astrocytes.

We describe the induction of Ia on cultured astrocytes by measles virus and the amplification of this induction by tumor necrosis factor (TNF). Measles virus induces Ia on rat astrocytes by direct interaction with these cells. TNF does not induce significant levels of Ia at any dose from 1 to 10,000 units/ml. As little as 10 units of TNF per ml, however, amplifies Ia-inducing signals generated by measles virus in astrocytes. In contrast, TNF and measles virus induce class I major histocompatibility complex (MHC) antigens, when applied individually, and TNF amplification of measles virus class I MHC induction is not apparent. The induction of either Ia or class I MHC antigens on rat astrocytes by measles virus does not depend on glial-derived soluble factors generated during infection. Since brain cells are normally lacking MHC antigens upon which T cells depend for interaction with antigen presenting cells, these data indicate that the ability of measles virus to directly stimulate MHC antigen expression and the ability of TNF to amplify Ia expression locally in the brain may be important in initiating cell-mediated immune response to viral infection.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1987

Cellular oncogenes and lymphocyte activation.

In normal mouse splenic B and T cells at least two cellular proto-oncogenes are expressed, i.e. c-myc and c-fos. The expression of c-myc depends on the activation of the cells, but not on subsequent growth. C-fos gene expression appears to be induced by the manipulation involved in preparation of single cell suspensions from spleens. In that respect, c-fos gene expression does not qualify as being significantly involved in transition from G O to S phase while expression of c-myc seems to be correlated with some early events of cell activation leading to growth competence. The kinetics and extent of c-myc gene expression vary with the mitogen used and the type of lymphocyte investigated as examplified by T cells and subpopulations thereof. The expression of both proto-oncogenes in normal mouse spleen cells is finely regulated by an interplay of transcriptional and post-transcriptional control mechanisms. These mechanisms operate differently for the two genes and independently from one another. They also change in predominance at various times, again independently from one another. While we have no evidence that c-fos has significance for the activation of lymphocytes, c-myc is a good candidate for being involved. Thus studies by Susan Corey and collaborators on transgenic mice which constitutively express c-myc in cells of the lymphocyte lineage, indicate that this lineage is profoundly affected. Among others, the effects concern the balance between proliferation and maturation and a constitutive high level of Ia expression, normally only observed in activated cells. Constitutive high expression of c-myc in B cells of these transgenic mice also makes them prone to leukemia possibly due to a series of subsequent events. These last findings also provide an explanation for the need for a very finely tuned regulation of c-myc gene expression as it is here described.

Animals↗
PubMed1986

Kinetics of cellular oncogene expression in mouse lymphocytes. I. Expression of c-myc and c-ras-Ha in T lymphocytes induced by various mitogens.

Murine splenic T lymphocytes display maximal cellular myc gene (c-myc) expression already 3 h after concanavalin A stimulation and subsequent down-regulation before the onset of DNA synthesis. Stimulation by leucoagglutinin in the presence or absence of interleukin 2 leads to only low initial levels of c-myc-specific RNA which, however, increase later on. A similar pattern of c-myc expression is shown by the Lyt-2+ T cell subpopulation stimulated with either concanavalin A or leucoagglutinin in the presence of interleukin 2. Although [3H]thymidine incorporation was identical, the leucoagglutinin-stimulated Lyt-2+ T cells were void of any demonstrable c-myc-specific RNA at 3 h post-stimulation. Thus, the kinetics of c-myc expression in mouse T lymphocytes are not at all uniform, but depend on the mitogen and the subpopulation. In contrast, levels of c-ras-Ha-specific RNA were always low at early times, always increased towards the onset of DNA synthesis and down-regulation was not observed.

Agglutinins↗
PubMed1985

IgM RNA switch from membrane to secretory form is prevented by adding antireceptor antibody to bacterial lipopolysaccharide-stimulated murine primary B-cell cultures.

Bacterial lipopolysaccharide (LPS) induces proliferation of resting primary murine B lymphocytes and their differentiation into Ig-secreting cells. This is accompanied by an increase in the rate of Ig gene transcription and the accumulation of mu heavy chain secretory mRNA. Specific antiantigen receptor antibody (anti-mu) induces resting B cells to proliferation but not differentiation. Upon addition of both LPS and anti-mu to cultures, resting B cells again proliferate but do not differentiate. RNA transfer blots of the Ig mRNA 2 days after induction with LPS/anti-mu show a specific deficiency of the 2.4-kilobase (kb) mu secretory mRNA, whereas the levels of the 2.7-kb mu membrane and 1.2-kb kappa light chain mRNAs are as high as in cells treated with LPS alone. Between days 3 and 4 after treatment with both reagents, reductions of mu membrane and, to a smaller extent, kappa mRNA become apparent. As measured by nuclear run-on transcription experiments at day 2, the transcription rates of Ig mu and the Ig kappa transcription units are equal in both induction experiments. Only at later stages do the LPS/anti-mu-treated cells transcribe Ig genes at a lower rate. Thus, the anti-mu treatment, drastically reducing the mu secretory mRNA production at early stages, represents a negative regulation occurring primarily at the posttranscriptional level.

Animals↗
PubMed1985

Analysis of the negative allogeneic effect using B cells and helper T cell lines as an indicator system: B cells identified as target cells for suppression.

The target cells for H-2b T lymphocytes mediating a negative allogeneic effect in vitro were analyzed by using carrier-specific helper T cell lines of H-2b, H-2d, or F1 origin and hapten-primed T-depleted spleen cells also expressing one or both of these haplotypes. The helper T cell lines were shown to be carrier specific and H-2b or H-2d restricted. Most importantly, the lines derived from H-2b homozygous mice were devoid of alloreactivity against H-2d and vice versa. Titration of naive H-2b T lymphocytes to the indicator cultures resulted in suppression of the secondary anti-DNP response of the indicator cells whenever the B cells expressed H-2d antigens. The lack of suppression observed in mixtures in which only the helper T cell lines expressed H-2d antigens was not reversed by the increased addition of naive H-2bxd cells, indicating that an insufficient amount of H-2d antigens present on the low number of helper T cells used did not account for this finding. Moreover, the polyclonal plaque-forming cell responses of F1 spleen cells to LPS were also suppressed by naive parental T cells. From these findings it is concluded that the suppressor T cells directly recognize and inhibit allogeneic B cells without the involvement of helper T cells. In addition, it was shown that the suppression of secondary anti-hapten responses by naive allogeneic T cells is blocked by monoclonal anti-Lyt-2 antibody added at the onset of culture. Addition late in culture had no effect, pointing to a functional role of the Lyt-2-bearing structure at an early stage of the suppressive events resulting in the negative allogeneic effect.

Animals↗
PubMed1979

[Soluble mediators as a means of communication between lymphozytes in immune reactions (author's transl)].

Soluble mediators play an important role in the positive and negative regulation of immune reactions. This has been particularly well documented for T-B-cooperation in the humoral immune response to T-dependent antigens. T-helper cells produce a T-cell replacing Factor (TRF) upon mitogenic or antigenic stimulation. It provides the signal to antigen triggered B-cells to begin with active antibody synthesis and secretion and thus it is a positively regulating mediator. Additional functional and some structural characteristics of TRF are described. Antigen specific and non-specific suppressor factors seem to be involved in the negative regulation of immune responses. Thus, the communication between cells of the immune system is largely conducted via soluble signal substances.

Antibody Formation↗