A5015483877- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Cell Adhesion Molecules Research
- Cellular Mechanics and Interactions
- Signaling Pathways in Disease
- Immunotherapy and Immune Responses
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Genomics, phytochemicals, and oxidative stress
- Psoriasis: Treatment and Pathogenesis
- Piperaceae Chemical and Biological Studies
- IL-33, ST2, and ILC Pathways
- Immune Response and Inflammation
- Ion Channels and Receptors
- Flavonoids in Medical Research
- Natural product bioactivities and synthesis
- Cytokine Signaling Pathways and Interactions
- S100 Proteins and Annexins
- Heat shock proteins research
- Redox biology and oxidative stress
- Cancer Research and Treatments
- Bioactive Compounds and Antitumor Agents
- NF-κB Signaling Pathways
- Mast cells and histamine
- Biochemical Analysis and Sensing Techniques
- Olfactory and Sensory Function Studies
University Hospital Heidelberg
2017-2024
Heidelberg University
2011-2024
The activity and function of T-cells are influenced by the intra- extracellular redox milieu. Oxidative stress induces hypo-responsiveness untransformed T-cells. Vice versa increased glutathione (GSH) levels or decreased reactive oxygen species (ROS) prime T-cell metabolism for inflammation, e.g. in rheumatoid arthritis (RA). Therefore, balancing milieu may represent a promising new option therapeutic immune modulation. Here we show that sulforaphane (SFN), compound derived from plants...
Oxidative stress leads to T-cell hyporesponsiveness or death. The actin-binding protein cofilin is oxidized during oxidative stress, which provokes a stiff actin cytoskeleton and hyporesponsiveness. Here, we show that long-term translocation of into the mitochondria necrotic-like programmed cell death (PCD) in human T cells. Notably, mutants functionally mimic oxidation by single mutation at oxidation-sensitive cysteins (Cys-39 Cys-80) predominately localize within mitochondria. expression...
Formation of immune synapses (IS) between T cells and APC requires multiple rearrangements in the actin cytoskeleton selective receptor accumulation supramolecular activation clusters (SMAC). The inner cluster (central SMAC) contains TCR/CD3 complex. outer (peripheral integrin LFA-1 Talin. Molecular mechanisms selectively stabilizing receptors IS remained largely unknown. Here, we demonstrate that sustained clustering is a consequence combined activities actin-bundling protein L-plastin...
Abstract Background Tumor cell migration and metastasis require dynamic rearrangements of the actin cytoskeleton. Interestingly, F-actin cross-linking stabilizing protein L-plastin, originally described as a leukocyte specific protein, is aberrantly expressed in several non-hematopoietic malignant tumors. Therefore, it has been discussed tumor marker. However, systematic vivo analyses functional relevance L-plastin for were so far lacking. Methods We investigated expression phosphorylation...
Chronic inflammation is a hallmark of chronic wounds and inflammatory skin diseases. Due to hyperactive prolonged triggered by proinflammatory immune cells, transitioning the repair healing phase halted. T cells may exacerbate milieu secreting cytokines.
Activation of naïve T cells requires costimulation via TCR/CD3 plus accessory receptors, which enables the dynamic rearrangement actin cytoskeleton and immune synapse maturation. Signaling events induced following may thus be valuable targets for therapeutic immunosuppression. Phosphorylation actin-bundling protein L-plastin represents such a costimulatory signal in primary human cells. Phosphorylated has higher affinity toward F-actin. However, importance phosphorylation regulation upon...
Abstract Several antitumor therapies work by increasing reactive oxygen species (ROS) within the tumor micromilieu. Here, we reveal that L-plastin (LPL), an established marker, is reversibly regulated ROS-induced thiol oxidation on Cys101, which forms a disulfide bridge with Cys42. LPL reduction mediated Thioredoxin1 (TRX1) system, as shown TRX1 trapping, knockdown and blockade of reductase (TRXR1) auranofin. diminishes its actin-bundling capacity. Ratiometric imaging using LPL-roGFP-Orp1...
Calcium signals in stimulated T cells are generally considered single entities that merely trigger immune responses, whereas costimulatory events specify the type of reaction. Here we show "T cell calcium signal" is a composite signal harboring two distinct components antagonistically control genomic programs underlying response. Using human from healthy individuals, establish nuclear as key adaptogenomics drives activation and required for signaling to cyclic adenosine monophosphate...
Piperlongumine (PL), a natural small molecule derived from the Piper longum Linn plant, has received growing interest as prooxidative drug with promising anticancer properties. Yet, influence of PL on primary human T cells remained elusive. Knowledge this is crucial importance, however, since in particular play critical role tumor control. Therefore, we investigated effects survival and function peripheral blood (PBTs). While was not cytotoxic to PBTs, it interfered several stages cell...
Cytotoxic T-cells (CTLs) play an important role in many immune-mediated inflammatory diseases. Targeting cytotoxicity of CTLs would allow to interfere with tissue destruction. Here we demonstrate that WF-10, a pro-oxidative compound, inhibits CTL-mediated cytotoxicity. WF-10 did not influence early steps target-cell killing, but impaired the ability detach from initial target cell and move second cell. This reduced serial killing was accompanied by stronger enrichment adhesion molecule LFA-1...
Oxidative stress can lead to T cell hyporesponsiveness. A reducing micromilieu (e.g. provided by dendritic cells) rescue cells from such oxidant-induced dysfunction. However, the effects on proteins leading restored activation remained unknown. One key molecule of is actin-remodeling protein cofilin, which dephosphorylated serine 3 upon costimulation and has an essential role in formation mature immune synapses between antigen-presenting cells. Cofilin spatiotemporally regulated; at plasma...
While several protein serine/threonine kinases control cytokine production by T cells, the roles of phosphatases are largely unexplored. Here, we analyzed involvement phosphatase 1α (PP1α) in synthesis following costimulation primary human cells. Small interfering RNA (siRNA)-mediated knockdown PP1α (PP1KD) or expression a dominant negative (D95N-PP1) drastically diminished interleukin-10 (IL-10) production. Focusing on key transcriptional activator IL-10, demonstrate that nuclear...
Cofilin is an essential actin remodeling protein promoting depolymerization and severing of filaments. To address the relevance cofilin for development function T cells in vivo, we generated knock-in mice which T-cell–specific nonfunctional (nf) was expressed instead wild-type (WT) cofilin. Nf lacked peripheral αβ showed a severe thymus atrophy. This caused by early developmental arrest thymocytes at double negative (DN) stage. Importantly, even though DN TCRβ chain intracellularly, they...
In psoriasis and other inflammatory skin diseases, keratinocytes (KCs) secrete chemokines that attract T cells, which, in turn, cause epidermal hyperplasia by secreting proinflammatory cytokines. To date, it remains unclear whether skin-homing particularly memory can also be activated direct cell contact with KCs. this study, we demonstrated the ability of primary human KCs to activate cells directly transmitting costimulatory signals through CD6/CD166/CD318 axis. Interestingly, despite...
Sulforaphan (SFN), ein natürlicher Nahrungsbestandteil in Kreuzblütengewächsen (z.B. Brokkoli), findet im Kontext möglicher Therapien bei Tumorerkrankungen zunehmend Beachtung. Mehrere Studien berichten über einen hemmenden Effekt auf das Wachstum von Tumorzellen und eine stark antioxidative Wirkung [1 – 4]. Krebsabwehr Immunsystem sind eng miteinander verzahnt. Eine intakte Immunantwort erkennt entartete eliminiert sie. Inwieweit SFN auch immunmodulierend wirkt, ist bisher wenig bekannt.