Taken together, we showed the occurrence of severe liver immunopathology upon LCMV infection in mice lacking Usp22 in their hematopoietic system, which was mostly related to reduced expression of PD-L1 on antigen-presenting cells and overactivation of virus-specific CD8+ T cells resulting in recruitment of neutrophil granulocytes and monocytes infiltrating the liver and inducing acute liver failure. Here, USP22 is linked to acute liver failure.