Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Usp22 Deficiency Switches Antiviral Response into Pathological CD8+ T Cell Activation via Downregulation of PD-L1

Justa Friebus-Kardash
* ORCID logo ,
Theresa Charlotte Christ
,
Nikolaus Dietlein
,
Abdelrahman Elwy
ORCID logo ,
Hossam Abdelrahman
,
Lisa Holnsteiner
,
Zhongwen Hu
,
Hans-Reimer Rodewald3
,
Karl Sebastian Lang
Version 1 : Received: 24 July 2023 / Approved: 10 August 2023 / Online: 11 August 2023 (08:58:08 CEST)

A peer-reviewed article of this Preprint also exists.

Friebus-Kardash, J.; Christ, T.C.; Dietlein, N.; Elwy, A.; Abdelrahman, H.; Holnsteiner, L.; Hu, Z.; Rodewald, H.-R.; Lang, K.S. Usp22 Deficiency Leads to Downregulation of PD-L1 and Pathological Activation of CD8+ T Cells and Causes Immunopathology in Response to Acute LCMV Infection. Vaccines 2023, 11, 1563. Friebus-Kardash, J.; Christ, T.C.; Dietlein, N.; Elwy, A.; Abdelrahman, H.; Holnsteiner, L.; Hu, Z.; Rodewald, H.-R.; Lang, K.S. Usp22 Deficiency Leads to Downregulation of PD-L1 and Pathological Activation of CD8+ T Cells and Causes Immunopathology in Response to Acute LCMV Infection. Vaccines 2023, 11, 1563.

Abstract

Ubiquitin-Specific-peptidase 22 (Usp22) cleaves ubiquitin moieties from numerous proteins, in particular transcription factors. Recently, it was reported that Usp22 acts as negative regulator of interferon-dependent responses. In the current study, we investigated the role of Usp22 deficiency upon acute viral infection with lymphocytic choriomeningitis (LCMV) virus. We found that lack of Usp22 on bone marrow derived cells (Usp22 fl/fl Vav1-Cre mice) reduced induction of type I and II interferons. Limited type I interferon response did not influence virus replication. However, restricted expression of PD-L1 led to increased frequencies of functional virus-specific CD8+ T cells and rapid death of Usp22 deficient mice. CD8+ T cell depletion experiments revealed that accelerated CD8+ T cells were responsible for enhanced lethality in Usp22 deficient mice. In conclusion, we found that the lack of Usp22 generated a pathological CD8+ T cell response, which gave rise to severe disease in mice.

Keywords

Ubiquitin-Specific-peptidase 22 (Usp22); LCMV; PD-L1 downregulation; activation of CD8+ T cells; iver failure

Subject

Medicine and Pharmacology, Immunology and Allergy

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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