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Thomas Höfer

Publications and source records attributed to Thomas Höfer.

17 recordsLinked to original sources
PubMed2006

NFATc1 autoregulation: a crucial step for cell-fate determination.

Nuclear factor of activated T cell c (NFATc) transcription factors appeared in evolution with the emergence of lymphocytes in jawed fish. They have decisive roles in the development of the immune system and adaptive immune responses. Following immunoreceptor stimulation, NFAT factors control the expression of a large set of genes and thereby the fate of peripheral lymphocytes. NFATc1 and NFATc2 are the most prominent NFAT factors in peripheral T cells; they overlap in their function but differ remarkably in the mode of expression. NFATc2 is constitutively synthesized in T cells, whereas the expression of NFATc1/alphaA, the most prominent of six NFATc1 isoforms in peripheral T cells, is strongly induced following T-cell receptor and co-receptor stimulation and maintained by positive autoregulation. Findings concerning NFATc1 autoregulation in peripheral T lymphocytes and other cells suggest that positive autoregulation of NFATc1 is a crucial step in cell-fate determination.

Amino Acid Sequence↗
PubMed2006

Models of IP3 and Ca2+ oscillations: frequency encoding and identification of underlying feedbacks.

Hormones that act through the calcium-releasing messenger, inositol 1,4,5-trisphosphate (IP3), cause intracellular calcium oscillations, which have been ascribed to calcium feedbacks on the IP3 receptor. Recent studies have shown that IP3 levels oscillate together with the cytoplasmic calcium concentration. To investigate the functional significance of this phenomenon, we have developed mathematical models of the interaction of both second messengers. The models account for both positive and negative feedbacks of calcium on IP3 metabolism, mediated by calcium activation of phospholipase C and IP3 3-kinase, respectively. The coupled IP3 and calcium oscillations have a greatly expanded frequency range compared to calcium fluctuations obtained with clamped IP3. Therefore the feedbacks can be physiologically important in supporting the efficient frequency encoding of hormone concentration observed in many cell types. This action of the feedbacks depends on the turnover rate of IP3. To shape the oscillations, positive feedback requires fast IP3 turnover, whereas negative feedback requires slow IP3 turnover. The ectopic expression of an IP3 binding protein has been used to decrease the rate of IP3 turnover experimentally, resulting in a dose-dependent slowing and eventual quenching of the Ca2+ oscillations. These results are consistent with a model based on positive feedback of Ca2+ on IP3 production.

Animals↗
PubMed2006

Adaptation of humoral memory.

Immunological memory, as provided by antibodies, depends on the continued presence of antibody-secreting cells, such as long-lived plasma cells of the bone marrow. Survival niches for these memory plasma cells are limited in number. In an established immune system, acquisition of new plasma cells, generated in response to recent pathogenic challenges, requires elimination of old memory plasma cells. Here, we review the adaptation of plasma cell memory to new pathogens. This adaptation is dependent upon the influx of plasmablasts, generated in a secondary systemic immune reaction, into the pool of memory plasma cells, the efficiency of competition of new plasmablasts with old plasma cells, and the frequency of infection with novel pathogens. To maintain old plasma cells at frequencies high enough to provide protection and to accommodate as many specificities as possible, an optimal influx rate per infection exists. This optimal rate is approximately three times higher than the minimal number of plasma cells providing protection. Influx rates of plasmablasts generated by vaccination approximately match this optimum level. Furthermore, the observed stability of serum concentrations of vaccine-specific antibodies implies that the influxing plasmablasts mobilize a similar number of plasma cells and that competitive infectious challenges are not more frequent than once per month.

Adaptation, Biological↗
PubMed2005

Kinetic models of phosphorylation cycles: a systematic approach using the rapid-equilibrium approximation for protein-protein interactions.

Activation-inactivation cycles of signalling proteins and transcription factors catalysed by kinases and phosphatases are a core component of cellular signal transduction. We present a systematic kinetic analysis of a phosphorylation cycle that starts from the description of elementary protein-protein interaction and catalytic steps. A rapid-equilibrium approximation for protein interactions is used to reduce the set of parameters. The resulting description consists of a kinetic equation for the phosphorylation of the target and a set of conservation conditions for kinase and phosphatase. Generally no explicit rate laws exist for the two enzymes; linear or Michaelis-Menten rate equations can be obtained in special cases. Key parameters that determine the stimulus-response curve and the response time of the cycle are the concentrations of kinase and phosphatase relative to the target protein and the affinities of the two enzymes for the different phosphorylation states of the target. Characterizing the response curve by the global response coefficient, we obtain a phase diagram that shows the existence of three kinds of behaviours: graded, ultrasensitive, and a previously undescribed biphasic response. Two kinds of competition effect turn out to shape the behaviour: (1) the degree of product inhibition of each enzyme, and (2) the competition between kinase and phosphatase to bind the target protein, as determined by their relative target affinities. The approach outlined here may be useful also for analysing more complex systems, including multiple phosphorylation and kinase cascades.

Computer Simulation↗
PubMed2005

Activation of the transcription factor NFAT1: concerted or modular regulation?

The transcription factor NFAT1 is activated through dephosphorylation of multiple serine residues, contained within the SRR1 and SP motifs. The phosphorylation status of these motifs regulates the subcellular localisation of NFAT1 via a conformational switch. Here, we discuss two molecular mechanisms for NFAT1 activation that resemble network-oriented approaches. In the modular mechanism, import and export are regulated separately by the SRR1 and SP motifs, respectively, whereas in the concerted model all residues jointly control both processes. Using simulations of a computational model, we show that both mechanisms may be compatible with recent experimental data on the import and export kinetics of NFAT1.

DNA-Binding Proteins↗
PubMed2005

Regulation of CD4+CD25+ regulatory T cell activity: it takes (IL-)two to tango.

Although CD4(+)CD25(+) regulatory T cells (Treg) represent a well-characterized population of T cells with in vitro and in vivo suppressive capacity, the basic mechanisms of suppression are still not understood. The constitutive expression of the high-affinity receptor for IL-2 has raised the question about the role of IL-2 in Treg function. Here, we review recent data indicating that IL-2 is not only necessary for the homeostasis of Treg but is also critical for the activation of Treg function. Since Treg do not produce IL-2 by themselves, their capacity to utilize IL-2 secreted by other T cells appears to be an essential component of Treg biology. This indicates that Treg suppressive activity is controlled by interaction with activated target cells via the soluble mediator IL-2. In Treg, IL-2 has been identified as a potent inducer of the immunosuppressive cytokine IL-10, an important mediator of Treg suppression in vivo. The efficient capture of IL-2 by Treg may, under conditions of limited IL-2 supply, cause IL-2 deprivation of responder T cells. This competition can explain some of the currently discussed discrepancies between in vivo and in vitro activity of Treg.

Animals↗
PubMed2005

On the kinetic design of transcription.

We analyse a stochastic model of transcription that describes transcription initiation by promoter activation and subsequent polymerase recruitment. Explicit expressions are derived for the control of an activator on the mean mRNA number and for the mRNA noise. Both properties are strongly influenced by the kinetics of promoter activation, mRNA synthesis and degradation. Low transcriptional noise is obtained either when the transcription initiation complex has a long life-time or when its components associate and dissociate rapidly. However, the ability of an activator to regulate the mRNA level is low in the first and high in the second case. Large noise is generated when the initial activation step of the promoter is slow. In this case, transcription can be burst-like; the mRNA distribution becomes bimodal while regulability of the mean copy number is maintained.

DNA-Directed RNA Polymerases↗
PubMed2004

Animal testing and alternative approaches for the human health risk assessment under the proposed new European chemicals regulation.

During the past 20 years the EU legislation for the notification of chemicals has focussed on new chemicals and at the same time failed to cover the evaluation of existing chemicals in Europe. Therefore, in a new EU chemicals policy (REACH, Registration, Evaluation and Authorization of Chemicals) the European Commission proposes to evaluate 30,000 chemicals within a period of 15 years. We are providing estimates of the testing requirements based on our personal experiences during the past 20 years. A realistic scenario based on an in-depth discussion of potential toxicological developments and an optimised "tailor-made" testing strategy shows that to meet the goals of the REACH policy, animal numbers may be significantly reduced below 10 million if industry would use in-house data from toxicity testing, which are confidential, if non-animal tests would be used, and if information from quantitative structure activity relationships (QSARs) would be applied in substance-tailored testing schemes. The procedures for evaluating the reproductive toxicity of chemicals have the strongest impact on the total number of animals bred for testing under REACH. We are assuming both an active collaboration with our colleagues in industry and substantial funding of the development and validation of advanced non-animal methods by the EU Commission, specifically in reproductive and developmental toxicity.

Animal Testing Alternatives↗
PubMed2004

Transcriptional control networks of cell differentiation: insights from helper T lymphocytes.

Coordinated programs of gene expression during cell differentiation can be controlled by master transcription factors. The differentiation of helper T (Th) lymphocytes during the immune response has been shown to occur along alternative pathways designated as Th1 and Th2. Induction of the Th1 and Th2 pathways is associated with the conversely regulated expression of the master factors T-bet and GATA-3, respectively. Both autoactivation and inhibition of GATA-3 play a crucial role in this process. We develop mathematical models of the underlying regulatory networks to provide a framework for the analysis of experimental data. Modeling concepts for gene expression dynamics are introduced, and paradigms for the behavior of gene-regulatory networks are reviewed. A mechanistic model for the regulation of GATA-3 in Th cells is developed that accounts for autoactivation and regulation by external differentiation signals. This system works as a bistable switch that enables the triggering of a differentiation program by transient inductive signals. GATA-3 inhibitors (such as FOG-1 and ROG) modulate GATA-3 expression by yet unidentified mechanisms. Three potential modes of inhibition, sequestration by a binding protein, repression of basal transcription, and repression of autoactivation, are predicted to have distinct, and strongly concentration-dependent, regulatory effects on GATA-3 dynamics. Based on these results, we develop a model for the cross-regulation of the alternative Th1 and Th2 differentiation programs which are governed by the dynamics of T-bet and GATA-3, respectively. The steady states of this model correlate with naïve, Th1-polarized, and Th2-polarized phenotypes. Our analysis makes predictions on the stability of the Th1 and Th2 programs and raises questions on the relation between transcription factor regulation and epigenetic determination in cell differentiation.

Animals↗
PubMed2004

New evidence for the theory of the stork.

Data from Berlin (Germany) show a significant correlation between the increase in the stork population around the city and the increase in deliveries outside city hospitals (out-of-hospital deliveries). However, there is no correlation between deliveries in hospital buildings (clinical deliveries) and the stork population. The decline in the number of pairs of storks in the German state of Lower Saxony between 1970 and 1985 correlated with the decrease of deliveries in that area. The nearly constant number of deliveries from 1985 to 1995 was associated with an unchanged stork population (no statistical significance). However, the relevance of the stork for the birth rate in that part of Germany remains unclear, because the number of out-of-hospital deliveries in this area is not well documented. A lack of statistical information on out-of-hospital deliveries in general is a severe handicap for further proof for the Theory of the Stork.

Animals↗
PubMed2003

Allosteric regulation of the transcription factor NFAT1 by multiple phosphorylation sites: a mathematical analysis.

NFAT transcription factors are activated through dephosphorylation by the phosphatase calcineurin. Experimental data show that 13 conserved phosphorylation sites conspire to control the transition between an inactive and an active conformation. We propose a quantitative model of the underlying molecular mechanisms that may generally apply to highly phosphorylated proteins. Mathematical analysis shows that multiple phosphorylation sites result in a threshold for protein activation. Its sharpness increases with the number of sites, thus providing a rationale for the involvement of the large number of serine residues in NFAT activation. The model predicts that nuclear kinases exert a larger control on the activation threshold than cytoplasmic kinases, and that the NFAT activation kinetics can discriminate between input signals of different amplitude.

Allosteric Regulation↗
PubMed2002

GATA-3 transcriptional imprinting in Th2 lymphocytes: a mathematical model.

Immunological memory involves the fast recall of cytokine expression by T helper (Th) lymphocytes. Two distinct profiles of cytokine expression, Th1 and Th2, can be induced by antigen and polarizing signals during activation of naive Th cells and can subsequently be reexpressed on stimulation by antigen alone. The transcription factor GATA-3 induces Th2 development. GATA-3 is activated by the Th2-polarizing stimulus, IL-4, and has recently been observed to autoactivate its transcription. Based on these experimental data, we developed a mathematical model of GATA-3 expression that assumes independent activation of GATA-3 transcription by IL-4 and by GATA-3. Cooperativity of GATA-3 transcriptional activation is shown to create a threshold for autoactivation, resulting in the coexistence of two distinct GATA-3 expression states: a state of basal expression and a state of high expression sustained by autoactivation. Suprathreshold IL-4 signals induce a transition from basal to high GATA-3 expression. Thus, GATA-3 autoactivation creates a bistable system that can memorize a transient inductive signal. The model further predicts conditions under which the state of high GATA-3 expression can be abolished, which may extinguish the Th2 cytokine memory.

Animals↗
PubMed2002

Control and plasticity of intercellular calcium waves in astrocytes: a modeling approach.

Intercellular Ca2+ waves in astrocytes are thought to serve as a pathway of long-range signaling. The waves can propagate by the diffusion of molecules through gap junctions and across the extracellular space. In rat striatal astrocytes, the gap-junctional route was shown to be dominant. To analyze the interplay of the processes involved in wave propagation, a mathematical model of this system has been developed. The kinetic description of Ca2+ signaling within a single cell accounts for inositol 1,4,5-trisphosphate (IP3) generation, including its activation by cytoplasmic Ca2+, IP3-induced Ca2+ liberation from intracellular stores and various other Ca2+ transports, and cytoplasmic diffusion of IP3 and Ca2+. When cells are coupled by gap junction channels in a two-dimensional array, IP3 generation in one cell triggers Ca2+ waves propagating across some tens of cells. The spatial range of wave propagation is limited, yet depends sensitively on the Ca2+-mediated regeneration of the IP3 signal. Accordingly, the term "limited regenerative signaling" is proposed. The gap-junctional permeability for IP3 is the crucial permissive factor for wave propagation, and heterogeneity of gap-junctional coupling yields preferential pathways of wave propagation. Processes involved in both signal initiation (activation of IP3 production caused by receptor agonist) and regeneration (activation of IP3 production by Ca2+, loading of the Ca2+ stores) are found to exert the main control on the wave range. The refractory period of signaling strongly depends on the refilling kinetics of the Ca2+ stores. Thus the model identifies multiple steps that may be involved in the regulation of this intercellular signaling pathway.

Animals↗
PubMed2002

Modelling of simple and complex calcium oscillations. From single-cell responses to intercellular signalling.

This review provides a comparative overview of recent developments in the modelling of cellular calcium oscillations. A large variety of mathematical models have been developed for this wide-spread phenomenon in intra- and intercellular signalling. From these, a general model is extracted that involves six types of concentration variables: inositol 1,4,5-trisphosphate (IP3), cytoplasmic, endoplasmic reticulum and mitochondrial calcium, the occupied binding sites of calcium buffers, and the fraction of active IP3 receptor calcium release channels. Using this framework, the models of calcium oscillations can be classified into 'minimal' models containing two variables and 'extended' models of three and more variables. Three types of minimal models are identified that are all based on calcium-induced calcium release (CICR), but differ with respect to the mechanisms limiting CICR. Extended models include IP3--calcium cross-coupling, calcium sequestration by mitochondria, the detailed gating kinetics of the IP3 receptor, and the dynamics of G-protein activation. In addition to generating regular oscillations, such models can describe bursting and chaotic calcium dynamics. The earlier hypothesis that information in calcium oscillations is encoded mainly by their frequency is nowadays modified in that some effect is attributed to amplitude encoding or temporal encoding. This point is discussed with reference to the analysis of the local and global bifurcations by which calcium oscillations can arise. Moreover, the question of how calcium binding proteins can sense and transform oscillatory signals is addressed. Recently, potential mechanisms leading to the coordination of oscillations in coupled cells have been investigated by mathematical modelling. For this, the general modelling framework is extended to include cytoplasmic and gap-junctional diffusion of IP3 and calcium, and specific models are compared. Various suggestions concerning the physiological significance of oscillatory behaviour in intra- and intercellular signalling are discussed. The article is concluded with a discussion of obstacles and prospects.

Animals↗