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

Kristina M Geiger; Michael Manoharan; Rachel Coombs; Kathya Arana; Chan-Su Park; Angus Y Lee; Nilabh Shastri; Ellen A Robey; Laurent Coscoy

doi:10.1016/j.celrep.2023.112317

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

Cell Rep. 2023 Apr 25;42(4):112317. doi: 10.1016/j.celrep.2023.112317. Epub 2023 Mar 29.

Authors

Kristina M Geiger¹, Michael Manoharan², Rachel Coombs², Kathya Arana², Chan-Su Park³, Angus Y Lee⁴, Nilabh Shastri³, Ellen A Robey⁵, Laurent Coscoy⁶

Affiliations

¹ Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720, USA; Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
² Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
³ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Cancer Research Lab, University of California, Berkeley, Berkeley, CA 94720, USA.
⁵ Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720, USA; Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: [email protected].
⁶ Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720, USA; Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: [email protected].

Abstract

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.

Keywords: CP: Immunology; ERAAP; QFL T cells; anti-viral; immune evasion; immune surveillance; murine cytomegalovirus; non-classical Qa-1b; unconventional.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aminopeptidases / metabolism
Animals
Antigen Presentation*
CD8-Positive T-Lymphocytes
Endoplasmic Reticulum / metabolism
Histocompatibility Antigens Class I / metabolism
Leucyl Aminopeptidase / metabolism
Mice
Muromegalovirus*
Peptides / metabolism

Substances

Aminopeptidases
Histocompatibility Antigens Class I
Leucyl Aminopeptidase
Peptides
ERAP1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding