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 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 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 locus demonstrated that CD8 T cells were unable to activate "poised" enhancer elements compared with wild-type CD8 T cells, correlating with diminished 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.