title: Dynamic regulation of permissive histone modifications and GATA3 binding underpin acquisition of granzyme A expression by virus-specific CD8(+) T cells.
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.
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Michelle L T
authors.initials: ML
authors.lastname: Nguyen
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Lauren
authors.initials: L
authors.lastname: Hatton
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Moshe
authors.initials: M
authors.lastname: Olshansky
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.|WHO Collaborating Centre for Reference and Research on Influenza, Victorian Infectious Diseases Reference Laboratory; at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Anne
authors.initials: A
authors.lastname: Kelso
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Brendan E
authors.initials: BE
authors.lastname: Russ
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Turner
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D053804:Granzymes / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D007156:Immunologic Memory; D009980:Influenza A virus / Q000276:immunology*; D015847:Interleukin-4 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D011499:Protein Processing, Post-Translational; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology
chemical_list: D000956:Antigens, Viral; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D006657:Histones; D050800:STAT6 Transcription Factor; D015847:Interleukin-4; D053804:Granzymes; C000597315:granzyme A, mouse
keywords: Cytotoxic T cell; Epigenetics; GATA3; Granzyme A; Influenza A virus