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Cytokine-Induced Cell Exhaustion to Mitigate Hyperinflammation

by Tommaso Marchetti, Samantha Milanesi, Diana Tintor, Tiziana Lorenzini, Severin Walser, Stefano Vavassori, Onur Boyman, and Jana Pachlopnik Schmid

Posted: August 12, 2024
Server: bioRxiv
DOI: 10.1101/2024.08.12.607544

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-2’s 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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