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Human hepatitis virus cohort studies have previously identified MHC\u2010I molecules as promising predictors of viral clearance. However, the underlying functional significance of these predictions is not fully understood. Here, we show that expression of single MHC\u2010I isomers promotes virus\u2010induced liver immunopathology. Specifically, using the lymphocytic choriomeningitis virus (LCMV) model system, we found MHC\u2010I proteins to be highly up\u2010regulated during infection. Deletion of one of the two MHC\u2010I isomers histocompatibility antigen 2 (H2)\u2013Db or H2\u2010Kb in C57Bl\/6 mice resulted in CTL activation recognizing the remaining MHC\u2010I with LCMV epitopes in increased paucity. This increased CTL response resulted in hepatocyte death, increased caspase activation, and severe metabolic changes in liver tissue following infection with LCMV. Moreover, depletion of CTLs abolished LCMV\u2010induced pathology in these mice with resulting viral persistence. In turn, natural killer (NK) cell depletion further increased antiviral CTL immunity and clearance of LCMV even in the presence of a single MHC\u2010I isomer. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Our results suggest that uniform MHC\u2010I molecule expression promotes enhanced CTL immunity during viral infection and contributes to increased CTL\u2010mediated liver cell damage that was alleviated by CD8 or NK cell depletion.<\/jats:p>","DOI":"10.1002\/hep4.1913","type":"journal-article","created":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T06:26:54Z","timestamp":1644906414000},"page":"1620-1633","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":9,"title":["Single MHC\u2010I Expression Promotes Virus\u2010Induced Liver Immunopathology"],"prefix":"10.1097","volume":"6","author":[{"given":"Haifeng C.","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine II, Medical 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