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

Abstract

Summary The molecular mechanisms that regulate the rapid transcriptional changes that occur during cytotoxic T lymphocyte (CTL) proliferation and differentiation in response to infection are poorly understood. We have utilised ChIP-seq to assess histone H3 methylation dynamics within naïve, effector and memory virus-specific T cells isolated directly ex vivo after influenza A virus infection. Our results show that within naïve T cells, co-deposition of the permissive H3K4me3 and repressive H3K27me3 modifications is a signature of gene loci associated with gene transcription, replication and cellular differentiation. Upon differentiation into effector and/or memory CTL, the majority of these gene loci lose the repressive H3K27me3 while retaining the permissive H3K4me3 modification. In contrast, immune-related effector gene promoters within naïve T cells lacked the permissive H3K4me3 modification, with acquisition of this modification occurring upon differentiation into effector/memory CTL. Thus, coordinate transcriptional regulation of CTL genes with related functions is achieved using distinct epigenetic mechanisms.

Lineage relationship of CD8+ T cell subsets is revealed by progressive changes in the epigenetic landscape

“…The finding that genes associated with glycolysis and effector-function are largely associated with a progressive increase in permissive H3K4me3 modifications-and not a profound loss of repressive H3K27me3 marks-is consistent with the recent findings by Russ et al in which acquisition of H3K4me3 marks at immune-related effector gene promoters was observed with progressive differentiation into effector cytotoxic T cells. 24 In summary, the present study provides an initial roadmap of the genome-wide histone H3 lysine 4 (H3K4me3) and H3 lysine 27 (H3K27me3) trimethylation modifications that are respectively permissive and antagonistic toward gene expression in distinct stages of CD8 1 T-cell differentiation, including the recently identified T memory stem cell population. Sustained immunity to intracellular pathogens and cancer requires that CD8 1 T cells have the capacity for long-lived persistence and effector function long after their initial exposure to antigen.…”

T-Cell Receptor (TCR) Clonotype-Specific Differences in Inhibitory Activity of HIV-1 Cytotoxic T-Cell Clones Is Not Mediated by TCR Alone

“…Alternate TCR-independent mechanisms may modulate CD8 ϩ T-cell function, including the introduction of epigenetic changes into gene-regulatory elements of CD8 ϩ T-cell differentiation and function that can be transmitted to daughter cells and triggered by acute viral infection (49)(50)(51)(52)(53). For example, commitment of virus-specific CD8 ϩ T cells to an exhausted phenotype is reinforced by persistent demethylation of the PD-1 locus as described for lymphocytic choriomeningitis virus (LCMV) and HIV infections (54)(55)(56).…”

Epigenomic Profiling of Human CD4+ T Cells Supports a Linear Differentiation Model and Highlights Molecular Regulators of Memory Development

“…Genome-wide analysis of such epigenetic marks therefore allows for conclusions not only on the current gene expression status but also facilitates insights into the history and the future potential of cells. To date only a few studies on mouse Tmem cells have been published, reporting limited datasets (Crompton et al, 2016;Hashimoto et al, 2013;Komori et al, 2015;Russ et al, 2014). A deep and systematic genome-wide analysis of the epigenetic landscape during human CD4 + Tmem cell differentiation is currently lacking.…”