DExD/H-box helicase 9 intrinsically controls CD8+ T cell-mediated antiviral response through noncanonical mechanisms

Sci Adv. 2022 Feb 11;8(6):eabk2691. doi: 10.1126/sciadv.abk2691. Epub 2022 Feb 9.

Abstract

Upon virus infection, CD8+ T cell accumulation is tightly controlled by simultaneous proliferation and apoptosis. However, it remains unclear how TCR signal coordinates these events to achieve expansion and effector cell differentiation. We found that T cell-specific deletion of nuclear helicase Dhx9 led to impaired CD8+ T cell survival, effector differentiation, and viral clearance. Mechanistically, Dhx9 acts as the key regulator to ensure LCK- and CD3ε-mediated ZAP70 phosphorylation and ERK activation to protect CD8+ T cells from apoptosis before proliferative burst. Dhx9 directly regulates Id2 transcription to control effector CD8+ T cell differentiation. The DSRM and OB_Fold domains are required for LCK binding and Id2 transcription, respectively. Dhx9 expression is predominantly increased in effector CD8+ T cells of COVID-19 patients. Therefore, we revealed a previously unknown regulatory mechanism that Dhx9 protects activated CD8+ T cells from apoptosis and ensures effector differentiation to promote antiviral immunity independent of nuclear sensor function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology*
  • Arenaviridae Infections / immunology
  • Arenaviridae Infections / metabolism
  • Arenaviridae Infections / pathology
  • Arenaviridae Infections / prevention & control*
  • CD8-Positive T-Lymphocytes / immunology*
  • COVID-19 / immunology
  • COVID-19 / metabolism
  • COVID-19 / pathology
  • COVID-19 / prevention & control*
  • Cell Differentiation
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • Humans
  • Immunity, Innate*
  • Lymphocyte Activation
  • Lymphocytic choriomeningitis virus / physiology
  • Mice
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • SARS-CoV-2 / physiology
  • Virus Replication

Substances

  • Antiviral Agents
  • Dhx9 protein, mouse
  • Neoplasm Proteins
  • DHX9 protein, human
  • DEAD-box RNA Helicases