Proposed model of FHL pathophysiology. In the traditional paradigm (left circle, connected by black arrows), antigen-presenting cells (APCs) and LCMV-infected cells present viral antigens to LCMV-specific T cells, activating them to secrete IFNγ. IFNγ acts back on APCs to enhance their ability to present antigen, setting up a positive feedback loop. In Prf1^−/− mice, T cells are unable to eliminate APCs via perforin, resulting in a loss of negative regulation that enables feed-forward amplification of inflammation. In our revised model, IL-33 signaling (right circle, connected by white arrows) further amplifies this vicious cycle. Tissue damage and cell death leads to the release of IL-33, which acts either directly or indirectly on LCMV-specific T cells to further promote their production of IFNγ. Elevated IFNγ exacerbates immunopathology, leading to further release of IL-33 from dying cells.