Walser, S. | bioRxiv Science

bioRxiv2024

Cytokine-Induced Cell Exhaustion to Mitigate Hyperinflammation

Haemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory disorder often driven by dysfunctional cytotoxic CD8+ T cells, is marked by cytokine storms, which may follow viral infections. In a study of a perforin-deficient mouse model of HLH with a viral trigger, we aimed to determine if CD8+ T cell behaviour could be modulated by targeted interleukin (IL)-2 treatment. We observed a paradoxical benefit that contrasted with IL-2s typical role in boosting T cell activity: targeted IL-2 delivery to CD8+ T cells led to reduced hyperinflammation and disease severity. Our results demonstrated that IL-2 induced exhaustion in overactive CD8+ T cells, thus mitigating hyperinflammation. These findings highlight the context-dependency of cytokine treatment and suggest new therapeutic strategies for HLH and other inflammatory diseases by leveraging cell exhaustion.

immunology↗

bioRxiv2023

Phosphorylation-controlled cohesion of a nuclear condensate regulates mRNA retention

Nuclear speckles are membraneless organelles that associate with active transcription sites and participate in post-transcriptional mRNA processing. During the cell cycle, nuclear speckles dissolve following phosphorylation of their protein components. Here, we identify the PP1 family as the phosphatases that counteract kinase-mediated dissolution. PP1 overexpression increases speckle cohesion and leads to retention of polyadenylated RNA within speckles and the nucleus. Using APEX2 proximity labeling combined with RNA-sequencing, we characterized the relationship between the cohesion of nuclear speckles and the recruitment of specific RNAs. We find that many transcripts are preferentially enriched within nuclear speckles compared to the nucleoplasm, particularly chromatin- and nucleus-associated transcripts. While total polyadenylated RNA retention increased with nuclear speckle cohesion, the ratios of most mRNA species to each other were constant, indicating non-selective, or proportional, retention. We then explored whether nuclear speckle cohesion changes in response to environmental perturbations associated with changes in kinase or phosphatase activity. We found that cellular responses to heat shock, oxidative stress, and hypoxia include changes to the cohesion of nuclear speckles and mRNA retention. Our results demonstrate that tuning the material properties of nuclear speckles provides a mechanism for the acute control of mRNA localization.

cell biology↗