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

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

Cite this

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title = "Early T-bet expression ensures an appropriate CD8+ lineage–specific transcriptional landscape after influenza A virus infection",
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.",
author = "Prier, {Julia E.} and Jasmine Li and Gearing, {Linden J.} and Moshe Olshansky and Sng, {Xavier Y. X.} and Hertzog, {Paul J.} and Turner, {Stephen J.}",
year = "2019",
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doi = "10.4049/jimmunol.1801431",
language = "English",
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Early T-bet expression ensures an appropriate CD8+ lineage–specific transcriptional landscape after influenza A virus infection. / Prier, Julia E.; Li, Jasmine; Gearing, Linden J.; Olshansky, Moshe; Sng, Xavier Y. X.; Hertzog, Paul J.; Turner, Stephen J.

In: Journal of Immunology, Vol. 203, No. 4, 15.08.2019, p. 1044-1054.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Early T-bet expression ensures an appropriate CD8+ lineage–specific transcriptional landscape after influenza A virus infection

AU - Prier, Julia E.

AU - Li, Jasmine

AU - Gearing, Linden J.

AU - Olshansky, Moshe

AU - Sng, Xavier Y. X.

AU - Hertzog, Paul J.

AU - Turner, Stephen J.

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