Biology subjects

Claus, M.

Publications and source records attributed to Claus, M..

5 recordsLinked to original sources

bioRxiv2026

2B4 co-engagement promotes serial degranulation and killing by human NK cells

Activation of Natural Killer (NK) cells depends on the stimulation of a broad range of receptors. Here we use murine NIH3T3 target cells expressing defined human NK cell ligands to stimulate different aspects of NK cell activity and identify how distinct ligand-receptor interactions regulate different aspects of NK cell activation. B7H6, MICA, and CD20-bound obinutuzumab engaging NKp30, NKG2D, or CD16, respectively, were found to be potent inducers of activity in pre-stimulated NK cells. Combination of these ligands with CD48 to also stimulate 2B4 significantly increased degranulation and cytokine secretion, while PVR engaging DNAM-1 showed favorable effects only in combination with B7H6. Activating NK cell receptors were downregulated in a ligand-specific fashion, whereas CD16 and NKp46 were found to be downregulated depending on NK cell activation induced by other receptors. Co-stimulation via 2B4 in combination with either NKp30, NKG2D, or CD16 significantly enhanced NK cells to serially degranulate and kill multiple targets. Our systematic analysis unravels the complexity of different activating NK cell receptors and provides strategies to specifically tune NK cell reactivities for therapeutic applications.

immunology↗

bioRxiv2024

Modulating Prefrontal Cortex Activity to Alleviate Stress-Induced Working Memory Deficits: A Transcranial Direct Current (tDCS) Study

This study explores the impact of stress on working memory (WM) performance, and the potential mitigating effects of transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (dlPFC) and ventromedial prefrontal cortex (vmPFC). The study had a crossover, randomized, single-blind, sham-controlled design, with stress induction as within-subject and stimulation condition as between-subject factors. We assessed stress-induced WM deficits using aversive video clips to induce stress and a verbal n-back task to assess WM performance. We analyzed physiological (cortisol and heart rate), behavioral, and electroencephalographic (EEG) changes due to stress before, during, and after WM task performance and their modulation by tDCS. Stress impaired WM performance in the sham stimulation condition for the 3-back load, but not for 2-back or 4-back loads in the WM task, and was associated with elevated physiological stress markers. tDCS over the vmPFC led to better WM task performance while stimulation over the dlPFC did not. Active tDCS with both dlPFC and vmPFC stimulation blunted cortisol release in stress conditions compared to sham. The EEG analysis revealed potential mechanisms explaining the behavioral effects of vmPFC stimulation. vmPFC stimulation led to a decreased P200 event-related potential (ERP) component compared to the sham stimulation condition and resulted in higher task-related alpha desynchronization, indicating reduced distractions and better focus during task performance. This study thus shows that the vmPFC might be a potential target for mitigating the effects of stress on WM performance, and contributes to the development of targeted interventions for stress-related cognitive impairments. Significance StatementThis study investigates how stress impacts working memory performance and whether non-invasive brain stimulation can mitigate these effects. Using transcranial direct current stimulation (tDCS), we targeted specific brain areas in participants stressed by watching aversive videos. Stress reduced working memory performance and increased cortisol levels. However, tDCS applied to the ventromedial prefrontal cortex (vmPFC) improved task performance and blunted the cortisol response compared to a sham treatment. EEG data suggest that stimulation also enhanced focus during task performance and reduced emotional distraction. Our findings suggest that tDCS over the vmPFC could be a promising non-invasive brain stimulation method to counteract the negative effects of stress on cognitive functions.

neuroscience↗

bioRxiv2024

Multimodal assessment of acute stress dynamics using an Aversive Video Paradigm (AVP)

This study explored the efficacy of inducing stress through aversive video clips and investigated its impact on psychological processes, brain, and vegetative physiology. It had a randomized, single-blinded, crossover design, where participants were exposed in separate sessions to aversive or neutral video clips. Subjective feelings of stress were assessed via questionnaires. Electroencephalography (EEG) with 62 electrodes was recorded continuously. EEG power and connectivity changes based on coherence were analyzed. Heart rate (HR) and heart rate variability (HRV) data were obtained during the whole experiment, and saliva was collected for cortisol and cytokine analysis at different time intervals. Subjective data showed increased anxiety and negative affect induced by the aversive video clips, accompanied by elevated salivary cortisol levels after exposure to the stressful clips, and decreased heart rate variability. Cytokine levels however increased over time in both control and stress conditions, which argues against a stress-specific alteration of cytokines in this specific stress protocol. EEG alterations during stress induction suggest a disruption of top-down control and increased bottom-up processing. These results show that aversive video clips are suited to induce psychological stress in an experimental setting reliably, and are associated with stress-specific emotional, and physiological changes.

neuroscience↗

bioRxiv2024

SARS-CoV-2 modulates NK cell responses via induction of HLA-E and triggers expansion of adaptive NK cells during acute infection

HLA-E expression plays a central role for modulation of NK cell function by interaction with inhibitory NKG2A and stimulatory NKG2C receptors on canonical and adaptive NK cells, respectively. Here, we demonstrate that infection of human primary lung tissue with SARS-CoV-2 leads to increased HLA-E expression and show that processing of the peptide YLQPRTFLL from the spike protein is primarily responsible for the strong, dose-dependent increase of HLA-E. Targeting the peptide site within the spike protein revealed that a single point mutation was sufficient to abrogate the increase in HLA-E expression. Spike-mediated induction of HLA-E differentially affected NK cell function: whereas degranulation, IFN-{gamma} production, and target cell cytotoxicity were enhanced in NKG2C+ adaptive NK cells, effector functions were inhibited in NKG2A+ canonical NK cells. Analysis of a cohort of COVID-19 patients in the acute phase of infection revealed that adaptive NK cells were induced irrespective of the HCMV status, challenging the paradigm that adaptive NK cells are only generated during HCMV infection. During the first week of hospitalization, patients exhibited a selective increase of early NKG2C+CD57- adaptive NK cells whereas mature NKG2C+CD57+ cells remained unchanged. Further analysis of recovered patients suggested that the adaptive NK cell response is primarily driven by a wave of early adaptive NK cells during acute infection that wanes once the infection is cleared. Together, this study suggests that NK cell responses to SARS-CoV-2 infection are majorly influenced by the balance between canonical and adaptive NK cells via the HLA-E/NKG2A/C axis.

immunology↗

bioRxiv2018

Single-fluorescent protein reporters allow parallel quantification of NK cell-mediated granzyme and caspase activities in single target cells

1.Natural killer (NK) cells eliminate infected and tumorigenic cells through delivery of granzymes via perforin pores or by activation of caspases via death receptors. In order to understand how NK cells combine different cell death mechanisms it is important to quantify target cell responses on a single cell level. However, currently existing reporters do not allow the measurement of several protease activities inside the same cell. Here we present a strategy for the comparison of two different proteases at a time inside individual target cells upon engagement by NK cells. We developed single-fluorescent protein reporters containing the RIEAD or the VGPD cleavage site for the measurement of granzyme B activity. We show that these two granzyme B reporters can be applied in combination with caspase-8 or caspase-3 reporters. While we did not find that caspase-8 was activated by granzyme B, our method revealed that caspase-3 activity follows granzyme B activity with a delay of about 6 minutes. Finally, we illustrate the comparison of several different reporters for granzyme A, M, K and H. The here presented approach is a valuable means for the investigation of the temporal evolution of cell death mediated by cytotoxic lymphocytes.

immunology↗