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J Immunol. 2019 Jun 21. pii: ji1801431. doi: 10.4049/jimmunol.1801431. [Epub ahead of print]

Early T-BET Expression Ensures an Appropriate CD8+ Lineage-Specific Transcriptional Landscape after Influenza A Virus Infection.

Author information

1
Department of Microbiology and Immunology, the Doherty Institute at the University of Melbourne, Parkville, Victoria 3010, Australia.
2
Department of Microbiology, Biomedical Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
3
Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; and.
4
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
5
Department of Microbiology and Immunology, the Doherty Institute at the University of Melbourne, Parkville, Victoria 3010, Australia; stephen.j.turner@monash.edu.au.

Abstract

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.

PMID:
31227580
DOI:
10.4049/jimmunol.1801431

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