Abstract
Naive CD8+ Tcell activation results in an autonomous program of cellular proliferation and differentiation. However, the mechanisms that underpin this process are unclear. Here, we profile genome-wide changes in chromatin accessibility, gene transcription, and the deposition of a key chromatin modification (H3K27me3) early after naive CD8+ Tcell activation. Rapid upregulation of the histone demethylase KDM6B prior to the first cell division is required for initiating H3K27me3 removal at genes essential for subsequent Tcell differentiation and proliferation. Inhibition of KDM6B-dependent H3K27me3 demethylation limits the magnitude of an effective primary virus-specific CD8+ Tcell response and the formation of memory CD8+ Tcell populations. Accordingly, we define the early spatiotemporal events underpinning early lineage-specific chromatin reprogramming that are necessary for autonomous CD8+ Tcell proliferation and differentiation.
Highlights
Upon virus infection, naive, cytotoxic T lymphocyte (CTL) activation results in a largely autonomous program of differentiation that results in proliferation and acquisition of lineage-specific effector functions (van Stipdonk et al, 2003)
BATF/JUN/IRF4 activity results in subsequent upregulation of other transcription factors (TFs), such as T-BET, RUNX3, and BLIMP1, which are all known to be essential for effective CD8+ T cell differentiation (Cruz-Guilloty et al, 2009; Kallies et al, 2009; Kurachi et al, 2014; Wang et al, 2018; Xin et al, 2016)
We observed upregulation across the time course of histone methyltransferases, such as Suv39h1/h2 and Ezh2/Suz12, that are associated with deposition of H3K9me3 (Rea et al, 2000) and H3K27me3 (Cao et al, 2002), respectively
Summary
Naive, cytotoxic T lymphocyte (CTL) activation results in a largely autonomous program of differentiation that results in proliferation and acquisition of lineage-specific effector functions (van Stipdonk et al, 2003). In contrast to naive CD8+ T cells, virus-specific memory CTLs are able to respond more readily and rapidly to subsequent infections without the need for further differentiation (Kaech et al, 2002; La Gruta et al, 2004; Lalvani et al, 1997; Oehen and Brduscha-Riem, 1998; Veiga-Fernandes et al, 2000). This function enables rapid control of a secondary infection, leading to immune protection. The activation of T-BET and RUNX3 consolidate commitment to the effector CTL lineage (Cruz-Guilloty et al, 2009; Intlekofer et al, 2005, 2008), whereas BLIMP1 is required for terminal
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