Distinct Epigenetic Signatures Delineate Transcriptional Programs during Virus-Specific CD8+ T Cell Differentiation

Russ, Brendan E.; Olshanksy, Moshe; Smallwood, Heather; Li, Jasmine; Denton, Alice E.; Stock, Angus T.; Croom, Hayley A; Cullen, Jolie G.; Nguyen, Michelle; Rowe, Stephanie; Olson, Matthew R.; Finkelstein, David; Kelso, Anne; Thomas, Paul G.; Speed, T. P.; Rao, Sudha; Turner, Stephen J.

doi:10.1016/j.immuni.2014.12.013

Cited by 30 publications

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“…The mechanisms described here may also help to account for the origins of a class of preexisting DHSs which are present in activated T cells and recruit FOXP3 during the course of regulatory T‐cell differentiation (Samstein et al , ). Taken together, this body of evidence supports the emerging view that the critical steps in establishing immunological memory do indeed occur early during the initial stages of naïve T‐cell activation, and not during the subsequent differentiation stages when additional cell type‐specific TFs get recruited (Badovinac et al , ; Kedzierska et al , ; Russ et al , ; Crompton et al , ).…”

Section: Discussionsupporting

confidence: 71%

Inducible chromatin priming is associated with the establishment of immunological memory in T cells

et al. 2016

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Immunological memory is a defining feature of vertebrate physiology, allowing rapid responses to repeat infections. However, the molecular mechanisms required for its establishment and maintenance remain poorly understood. Here, we demonstrated that the first steps in the acquisition of T‐cell memory occurred during the initial activation phase of naïve T cells by an antigenic stimulus. This event initiated extensive chromatin remodeling that reprogrammed immune response genes toward a stably maintained primed state, prior to terminal differentiation. Activation induced the transcription factors NFAT and AP‐1 which created thousands of new DNase I‐hypersensitive sites (DHSs), enabling ETS‐1 and RUNX1 recruitment to previously inaccessible sites. Significantly, these DHSs remained stable long after activation ceased, were preserved following replication, and were maintained in memory‐phenotype cells. We show that primed DHSs maintain regions of active chromatin in the vicinity of inducible genes and enhancers that regulate immune responses. We suggest that this priming mechanism may contribute to immunological memory in T cells by facilitating the induction of nearby inducible regulatory elements in previously activated T cells.

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Section: Discussionsupporting

confidence: 71%

Inducible chromatin priming is associated with the establishment of immunological memory in T cells

et al. 2016

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“…By contrast, trimethylation of lysine 27 (H3K27me3) is a correlate of transcriptional repression . Recently, it has been demonstrated that acquisition of granzyme B (GZMB) and perforin expression after naïve CD8 + T‐cell differentiation into effector CTLs was associated with enrichment at the gene promoters of histone modifications that promote gene transcription, namely H3K4me3 and H3K9Ac . Denton et al.…”

Section: Introductionmentioning

confidence: 99%

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

Nguyen

Hatton

et al. 2015

Eur J Immunol

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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 differentiationdependent 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.Keywords: Cytotoxic T cell r Epigenetics r GATA3 r Granzyme A r Influenza A virus Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionA cardinal feature of CD8 + T-cell immunity is the capacity to acquire lineage-specific effector functions that promote clearance of foreign pathogens and that are maintained into memory. Naïve CD8 + T cells are initially quiescent and need to undergo Correspondence: Prof. Stephen J. Turner e-mail: sjturn@unimelb.edu.au proliferation and differentiation upon activation to acquire effector functions and become effector cells [1,2]. Optimal naïve T-cell activation requires the integration of multiple signaling cascades that include cross-linking of the antigen-specific T-cell receptor (signal 1); costimulation (signal 2) and soluble factors such as cytokines (signal 3) [3,4]. In contrast, memory T cells are capable of triggering a more robust and rapid response upon subsequent exposure to the same antigen without the need to undergo extensive proliferation as their naïve counterparts [5,6]. Importantly, differences in the functional capacity between these C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 308Michelle L. T. Nguyen et al. Eur. J. Immunol. 2016. 46: 307-318 CD8 + T-cell subsets are underscored by coordinated changes in gene expression profiles [1,7]. The incorporation of covalently modified histone proteins within specific gene regulatory elements is a key mechanism for modulating gene transcription [8]. For example, acetylation of the histone H3 at lysine 9 (H3K9ac) within gene promoters correlates with t...

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“…The development and differentiation of immune cells, as well as innate and adaptive responses, are precisely regulated and is attributed in part by dynamic epigenetic modifications (Allan and Nutt, 2014;Alvarez-Errico et al, 2014;Ansel et al, 2003;Kioussis and Georgopoulos, 2007;Russ et al, 2014;Su and Tarakhovsky, 2005;Won et al, 2014). Here we present a comprehensive review of the epigenetic dynamics related to these processes as well as the role of epigenetics in the pathogenesis of autoimmune diseases.…”

Section: Q2mentioning

confidence: 99%

“…H3K9 hyperacetylation enhances the expression of Prf1 (Perforin) and Gzmb (GranzymeB) mRNA at the Prf1 and Gzmb gene loci, which are two transcriptional target genes in CD8 + T cells (Araki et al, 2008). A recent study demonstrated that permissive histone modifications such as H3K4me3 and repressive histone modifications such as H3K27me3 at certain gene loci act on the commitment, development and differentiation of cytotoxic T cells (CTLs) (Russ et al, 2014). During naïve T cell differentiation into effector and/or memory CTLs, most of the specific gene loci eliminate the repressive H3K27me3 modification and maintain the permissive H3K4me3 regulation (Russ et al, 2014).…”

Section: T Lymphocytes and Epigenetic Modifications (Figs 3 And 4)mentioning

confidence: 99%

“…A recent study demonstrated that permissive histone modifications such as H3K4me3 and repressive histone modifications such as H3K27me3 at certain gene loci act on the commitment, development and differentiation of cytotoxic T cells (CTLs) (Russ et al, 2014). During naïve T cell differentiation into effector and/or memory CTLs, most of the specific gene loci eliminate the repressive H3K27me3 modification and maintain the permissive H3K4me3 regulation (Russ et al, 2014). Chandele et al (2008) indicated that diacetylated histone H3 (diAcH3) is enriched in activated effector CTLs, which acquire a central memory phenotype.…”

Section: T Lymphocytes and Epigenetic Modifications (Figs 3 And 4)mentioning

confidence: 99%

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Epigenetic dynamics in immunity and autoimmunity

Zhao

Wang

Yung

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Distinct Epigenetic Signatures Delineate Transcriptional Programs during Virus-Specific CD8+ T Cell Differentiation

Cited by 30 publications

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Inducible chromatin priming is associated with the establishment of immunological memory in T cells

Inducible chromatin priming is associated with the establishment of immunological memory in T cells

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

Epigenetic dynamics in immunity and autoimmunity

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Distinct Epigenetic Signatures Delineate Transcriptional Programs during Virus-Specific CD8+ T Cell Differentiation

Cited by 30 publications

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Inducible chromatin priming is associated with the establishment of immunological memory in T cells

Inducible chromatin priming is associated with the establishment of immunological memory in T cells

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

Epigenetic dynamics in immunity and autoimmunity

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