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

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 <i>Id2</i> transcription to control effector CD8⁺ T cell differentiation. The DSRM and OB_Fold domains are required for LCK binding and <i>Id2</i> 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.