DExD/H-box helicase 9 intrinsically controls CD8 <sup>+</sup> T cell–mediated antiviral response through noncanonical mechanisms
Anjun Jiao, Chenming Sun, Xin Wang, Lei Lei, Haiyan Liu, Wenhui Li, Xiaofeng Yang, Huiqiang Zheng, Renyi Ding, Kun Zhu, Yanhong Su, Cangang Zhang, Lianjun Zhang, Baojun Zhang
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.