Cytokine-Induced Cell Exhaustion to Mitigate Hyperinflammation
Marchetti, T.; Milanesi, S.; Tintor, D.; Lorenzini, T.; Walser, S.; Vavassori, S.; Boyman, O.; Pachlopnik Schmid, J.
Show 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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