Early T-BET Expression Ensures an Appropriate CD8+ Lineage-Specific Transcriptional Landscape after Influenza A Virus Infection.
Julia E PrierJasmine LiLinden J GearingMoshe OlshanskyXavier Y X SngPaul J HertzogStephen J TurnerPublished in: Journal of immunology (Baltimore, Md. : 1950) (2019)
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 Tbx21 -/- 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.
Keyphrases
- transcription factor
- mouse model
- wild type
- genome wide
- gene expression
- single cell
- type diabetes
- poor prognosis
- metabolic syndrome
- dna methylation
- dendritic cells
- machine learning
- magnetic resonance
- electronic health record
- skeletal muscle
- heat stress
- data analysis
- working memory
- big data
- artificial intelligence
- hiv infected
- copy number
- dna binding
- climate change
- heat shock protein