Early T-bet expression ensures an appropriate CD8⁺ lineage–specific transcriptional landscape after influenza A virus infection

Virus infection triggers large-scale changes in the phenotype and function of naive CD8⁺ T cells, resulting in the generation of effector and memory T cells that are then critical for immune clearance. The T-BOX family of transcription factors (TFs) are known to play a key role in T cell differentiation, with mice deficient for the TF T-BET (encoded by Tbx21) unable to generate optimal virus-specific effector responses. Although the importance of T-BET in directing optimal virus-specific T cell responses is accepted, the precise timing and molecular mechanism of action remains unclear. Using a mouse model of influenza A virus infection, we demonstrate that although T-BET is not required for early CD8⁺ T cell activation and cellular division, it is essential for early acquisition of virus-specific CD8⁺ T cell function and sustained differentiation and expansion. Whole transcriptome analysis at this early time point showed that Tbx21 deficiency resulted in global dysregulation in early programming events with inappropriate lineage-specific signatures apparent with alterations in the potential TF binding landscape. Assessment of histone posttranslational modifications within the Ifng locus demonstrated that Tbx21²/² CD8⁺ T cells were unable to activate “poised” enhancer elements compared with wild-type CD8⁺ T cells, correlating with diminished Ifng transcription. In all, these data support a model whereby T-BET serves to promote appropriate chromatin remodeling at specific gene loci that underpins appropriate CD8⁺ T cell lineage–specific commitment and differentiation.