CD8 T Cell Memory Increases Immunopathology in the Perforin-Deficient Model of Hemophagocytic Lymphohistiocytosis Secondary to TNF-α

Abstract

Familial hemophagocytic lymphohistiocytosis type 2 (FHL2) is a cytokine storm syndrome characterized by immune hyperactivation with viral infection due to a CD8 T cell cytotoxic killing defect secondary to a perforin deficiency. As most studies of FHL2 mice have used pathogen-naive animals, the effects of immune memory on FHL2 are understudied. We used an immunization model of the perforin-deficient mouse to study the effects of immune memory on FHL2. Prior CD8 T cell–specific Ag exposure leads to enhanced hemophagocytic lymphohistiocytosis with increased morbidity and decreased time to mortality. Enhanced disease is associated with altered cytokine production and T cell proliferation. Response to IFN-γ blockade is reduced and TNF-α gains a pathogenic role, although blockade of the IL-33 receptor ST2 remains effective. These results suggest that pre-existing immune memory may worsen the outcome and alter the treatment response for FHL2 patients who may not be naive to their immune triggers.