Vaccines (Oct 2023)

Usp22 Deficiency Leads to Downregulation of PD-L1 and Pathological Activation of CD8<sup>+</sup> T Cells and Causes Immunopathology in Response to Acute LCMV Infection

  • Justa Friebus-Kardash,
  • Theresa Charlotte Christ,
  • Nikolaus Dietlein,
  • Abdelrahman Elwy,
  • Hossam Abdelrahman,
  • Lisa Holnsteiner,
  • Zhongwen Hu,
  • Hans-Reimer Rodewald,
  • Karl Sebastian Lang

DOI
https://doi.org/10.3390/vaccines11101563
Journal volume & issue
Vol. 11, no. 10
p. 1563

Abstract

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Ubiquitin-specific peptidase 22 (Usp22) cleaves ubiquitin moieties from numerous proteins, including histone H2B and transcription factors. Recently, it was reported that Usp22 acts as a negative regulator of interferon-dependent responses. In the current study, we investigated the role of Usp22 deficiency in acute viral infection with lymphocytic choriomeningitis virus (LCMV). We found that the lack of Usp22 on bone marrow-derived cells (Usp22fl/fl Vav1-Cre mice) reduced the induction of type I and II interferons. A 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.

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