The project will continue to define novel genetic causes for HLH in humans. Moreover, the principal investigators will join forces to explore and control hyperstimulation of T cells as key drivers of disease in primary HLH. The molecular control of hyperstimulated T cells will be studied in human and murine HLH models to position the functional state, molecular signature and the epigenetic state of these cells relative to that of acute effector and exhausted T cells. The overall idea is to identify pathways driving disease-associated T cells in HLH that are amenable to novel treatment approaches. One concept is to induce “therapeutic T cell exhaustion” in HLH by engaging inhibitory receptors. This builds on preliminary data showing that an agonistic PD-1-specific antibody enhancing negative signals to T cells can improve the clinical outcome of HLH in mice.