Dynamic regulation of permissive histone modifications and GATA3 binding underpin acquisition of granzyme A expression by virus-specific CD8+ T cells

Michelle L. T. Nguyen, Lauren Hatton, Jasmine Li, Moshe Olshansky, Anne Kelso, Brendan E. Russ, Stephen J. Turner

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

Abstract

Numerous studies have focused on the molecular regulation of perforin (PFP) and granzyme B (GZMB) expression by activated cytotoxic T lymphocytes (CTLs), but little is known about the molecular factors that underpin granzyme A (GZMA) expression. In vitro activation of naïve CD8+ T cells, in the presence of IL-4, enhanced STAT6-dependent GZMA expression and was associated with GATA3 binding and enrichment of transcriptionally permissive histone posttranslational modifications (PTMs) across the Gzma gene locus. While GZMA expression by effector influenza A virus specific CTLs was also associated with a similar permissive epigenetic signature, memory CTL lacked enrichment of permissive histone PTMs at the Gzma locus, although this was restored within recalled secondary effector CTLs. Importantly, GZMA expression by virus-specific CTLs was associated with GATA3 binding at the Gzma locus, and independent of STAT6-mediated signaling. This suggests regulation of GZMA expression is underpinned by differentiation-dependent regulation of chromatin composition at the Gzma locus and that, given GATA3 is key for CTL differentiation in response to infection, GATA3 expression is regulated by a distinct, IL-4 independent, signaling pathway. Overall, this study provides insights into the molecular mechanisms that control transcription of Gzma during virus-induced CD8+ T-cell differentiation.

Original languageEnglish
Pages (from-to)307-318
Number of pages12
JournalEuropean Journal of Immunology
Volume46
Issue number2
DOIs
Publication statusPublished - 1 Feb 2016
Externally publishedYes

Keywords

  • Cytotoxic T cell
  • Epigenetics
  • GATA3
  • Granzyme A
  • Influenza A virus

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