Interferon regulatory factor 4 sustains CD8⁺ T cell expansion and effector differentiation

Upon infection, CD8⁺ Tcells undergo a stepwise process of early activation, expansion, and differentiation into effector cells. How these phases are transcriptionally regulated is incompletely defined. Here, we report that interferon regulatory factor 4 (IRF4), dispensable for early CD8⁺ Tcell activation, was vital for sustaining the expansion and effector differentiation of CD8⁺ Tcells. Mechanistically, IRF4 promoted the expression and function of Blimp1 and T-bet, two transcription factors required for CD8⁺ Tcell effector differentiation, and simultaneously repressed genes that mediate cell cycle arrest and apoptosis. Selective ablation of Irf4 in peripheral CD8⁺ Tcells impaired antiviral CD8⁺ Tcell responses, viral clearance, and CD8⁺ Tcell-mediated host recovery from influenza infection. IRF4 expression was regulated by Tcell receptor (TCR) signaling strength via mammalian target of rapamycin (mTOR). Our data reveal that IRF4 translates differential strength of TCR signaling into different quantitative and qualitative CD8⁺ Tcell responses.