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

Julia E. Prier, Jasmine Li, Linden J. Gearing, Moshe Olshansky, Xavier Y. X. Sng, Paul J. Hertzog, Stephen J. Turner

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)1044-1054
Number of pages11
JournalJournal of Immunology
Volume203
Issue number4
DOIs
Publication statusPublished - 15 Aug 2019

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