In mouse model of HLH, targeted interleukin-2 therapy reduces hyperinflammation by inducing exhaustion in overactive immune cells.

Haemophagocytic lymphohistiocytosis (HLH, a life-threatening disorder often driven by dysfunctional cytotoxic CD8+ T cells) is characterized by cytokine storms, which may occur after viral infections. In a study of a perforin-deficient mouse model of HLH with a viral trigger, we sought to determine whether the behaviour of the CD8+ T cells could be modulated by targeted treatment with interleukin (IL)-2. We observed a paradoxical benefit that contrasted with IL-2's typical role in enhancing T cell cytotoxicity: targeted IL-2 delivery to CD8+ T cells was associated with less hyperinflammation and less intense signs of disease. Our results showed that IL-2 induced exhaustion in overactive CD8+ T cells and thus mitigated hyperinflammation. These findings emphasized the context-dependency of cytokine treatment and open up new perspectives for treating HLH and other inflammatory diseases by leveraging cell exhaustion.