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bioRxiv · 10.1101/2024.08.12.607544

Cytokine-Induced Cell Exhaustion to Mitigate Hyperinflammation

Marchetti, T.·Milanesi, S.·Tintor, D.·Lorenzini, T.·Walser, S.·Vavassori, S.·Boyman, O.·Pachlopnik Schmid, J.
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Abstract

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.

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Marchetti, T., Milanesi, S., Tintor, D., Lorenzini, T., Walser, S., Vavassori, S., Boyman, O., Pachlopnik Schmid, J.. 2024-08-12. Cytokine-Induced Cell Exhaustion to Mitigate Hyperinflammation. https://doi.org/10.1101/2024.08.12.607544

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