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

Abstract

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.

Rapid Recall Ability of Memory T cells is Encoded in their Epigenome

“…Recently, Bevington et al . uncovered the presence of stably maintained DNase-hypersensitive sites in the murine memory T cells42 which further supports our findings. Here we report that in human memory T cells positive chromatin modifications are also present in the vicinity of rapid recall genes.…”

A Transcription Factor Pulse Can Prime Chromatin for Heritable Transcriptional Memory

“…In line with our observation, a recent paper studying long-term memory in primary macrophages concluded that removal of repressive H3K9 methylation enabled transcriptional memory induced by LPS exposure (35). In future studies, it will be interesting to survey the nucleosome landscape to query whether nucleosome depletion occurring during Pol II elongation is another event that is inherited, as suggested in recent studies of transcriptional memory in mammalian cells (6,7).…”

Store-Operated Ca2+ Entry Controls Clonal Expansion of T Cells through Metabolic Reprogramming

“…In silico analyses of common transcription factor binding motifs revealed the presence of consensus NFAT binding motifs in the regulatory regions of Slc2a1 , Slc2a3 , Hk2, Aldoa, Pgk1, Eno1 as well as Myc, Irf4 and Hif1a . Analysis of DNase I hypersensitivity (Bevington et al, 2016) and ATAC-sequencing (Mognol et al, 2017) data from naïve and activated CD8 + T cells revealed open chromatin regions in the regulatory regions of Irf4, Slc2a3 (Figure 5A) as well as Hif1a, Myc, Slc2a1 and Hk2 (Figure S5A). To determine if NFAT binds to these open chromatin regions, we analyzed genome-wide ChIP-sequencing (ChIP-seq) data that report on the binding of NFATc2 in WT (and Nfatc2 -deficient) CD8 + T cells (Martinez et al, 2015) and NFATc1 in activated CD8 + T cells from a NFATc1 BAC-transgenic mouse line (Klein-Hessling, 2017).…”

“…NFATc2 ChIP-seq data (Martinez et al, 2015) and genome-wide NFATc1 chromatin binding data (using T cells from a BAC-transgenic mouse strain in which NFATc1 is endogenously biotinylated by the biotin-ligase BirA and precipitated using streptavidin beads) (Klein-Hessling, 2017) were aligned to open chromatin regions defined by DNase I hypersensitivity sites in naïve and CD8 + T cell blasts (Bevington et al, 2016) and accessible chromatin regions defined by ATAC-seq in resting and PMA/ionomycin-stimulated CD8 + T cells (Mognol et al, 2017). All sequencing data was mapped to the mouse mm9 genome assembly using the Bowtie software package.…”

“… (A) In silico analysis of Irf4 and Slc2a3 genes in CD8 + T cells for chromatin accessibility measured by DNase I hypersensitivity analysis (Bevington et al, 2016) and ATAC sequencing (Mognol et al, 2017) and binding of NFATc1 (Klein-Hessling, 2017) and NFATc2 (Martinez et al 2015). (B) Luciferase reporter analyses of the Slc2a3 promoter (Prom.)…”