Murine cytomegalovirus downregulates ERAAP and induces an unconventional T cell response to self

The endoplasmic reticulum aminopeptidase associated with antigen processing (ERAAP) plays a crucial role in shaping the peptide-major histocompatibility complex (MHC) class I repertoire and maintaining immune surveillance. While murine cytomegalovirus (MCMV) has multiple strategies for manipulating the antigen processing pathway to evade immune responses, the host has also developed ways to counter viral immune evasion. In this study, we find that MCMV modulates ERAAP and induces an interferon γ (IFN-γ)-producing CD8+ T cell effector response that targets uninfected ERAAP-deficient cells. We observe that ERAAP downregulation during infection leads to the presentation of the self-peptide FL9 on non-classical Qa-1b, thereby eliciting Qa-1b-restricted QFL T cells to proliferate in the liver and spleen of infected mice. QFL T cells upregulate effector markers upon MCMV infection and are sufficient to reduce viral load after transfer to immunodeficient mice. Our study highlights the consequences of ERAAP dysfunction during viral infection and provides potential targets for anti-viral therapies. [Display omitted] •MCMV downregulates ERAAP, leading to FL9 presentation on Qa-1b•MCMV infection induces non-classical, Qa-1b-restricted QFL T cells to proliferate•QFL T cells acquire an effector phenotype and protect against severe MCMV infection Geiger et al. find that MCMV downregulates MHC class I peptide-processing enzyme ERAAP. MCMV-infected mice develop a non-classical QFL T cell response, directed against ERAAP downregulated cells. QFL T cells protect against severe MCMV infection in immunodeficient mice. QFL T cells serve as an unconventional response against MCMV infection.