c-Myc uses Cul4b to preserve genome stability and promote CD8+ T cell-mediated antiviral immune responses
During infection, virus-specific CD8+ T cells undergo rapid bursts of proliferation and differentiate into effector cells that kill virus infected cells and reduce viral load. This rapid clonal expansion can put T cells at significant risk for replication-induced DNA damage. We found that c-Myc utilizes the E3 ubiquitin ligase, Cul4b, to inextricably link CD8+ T cell expansion to DNA damage response pathways. Following activation, c-Myc increased levels of Cul4b and other members of the CRL4 complex. Despite having abundant c-Myc expression, Cul4b-deficient CD8+ T cells were unable to expand and clear virus. Cul4b-deficient CD8+ T cells accrued DNA damage and succumbed to proliferative catastrophe early after antigen encounter. Mechanistically, Cul4b ablation induced a protracted accumulation of p21 and Cyclin E2 resulting in replication stress. Our data show that, to support cell proliferation, c-Myc must employ Cul4b to maintain genome stability, thereby directly coupling these two interdependent pathways. These data clarify how CD8+ T cells use c-Myc and Cul4b to sustain their potential for extraordinary population expansion, longevity and antiviral responses. Overall design: Comparative gene expression profiling analysis of RNA-seq data for purified CD8+ T cells from WT and Cul4b fl/fl CD4Cre mice.