CD8⁺ T Cell Biology in Cytokine Storm Syndromes

Familial forms of hemophagocytic lymphohistiocytosis (HLH) are caused by loss-of-function mutations in genes encoding perforin as well as those required for release of perforin-containing cytotoxic granule constituent. Perforin is expressed by subsets of CD8⁺ T cells and NK cells, representing lymphocytes that share mechanism of target cell killing yet display distinct modes of target cell recognition. Here, we highlight recent findings concerning the genetics of familial HLH that implicate CD8⁺ T cells in the pathogenesis of HLH and discuss mechanistic insights from animal models as well as patients that reveal how CD8⁺ T cells may contribute to or drive disease, at least in part through release of IFN-γ. Intriguingly, CD8⁺ T cells and NK cells may act differentially in severe hyperinflammatory diseases such as HLH. We also discuss how CD8⁺ T cells may promote or drive pathology in other cytokine release syndromes (CSS). Moreover, we review the molecular mechanisms underpinning CD8⁺ T cell-mediated lymphocyte cytotoxicity, key to the development of familial HLH. Together, recent insights to the pathophysiology of CSS in general and HLH in particular are providing promising new therapeutic targets.