Proposed model of the pathophysiology of HLH. (A) During a normal immune response, presentation of antigen promotes CD8⁺ T-cell responses. In return, CD8⁺ T cells secrete IFNγ, which activates antigen-presenting cells and further promotes antigen presentation. This positive feedback loop is restrained by perforin-dependent mechanisms. It remains unclear whether this occurs via specific destruction of professional antigen-presenting cells, general destruction of virally infected cells, or additional mechanisms. (B) In LCMV-infected pfp^–/– mice, the failure of perforin-dependent mechanisms allows for spiraling immune activation and excessive secretion of IFNγ. This leads to the development of an HLH-like syndrome.