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 DN ase I‐hypersensitive sites ( DHS s), enabling ETS ‐1 and RUNX 1 recruitment to previously inaccessible sites. Significantly, these DHS s remained stable long after activation ceased, were preserved following replication, and were maintained in memory‐phenotype cells. We show that primed DHS s 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. image Naïve T cells become epigenetically imprinted when activated and subsequently they stably maintain regions of accessible active chromatin bound by ETS 1 and RUNX 1. These primed DNA elements support efficient reactivation of inducible genes in previously activated T cells. Naïve T cells acquire a specific epigenetic imprint after initial T‐cell activation. Primed T cells and memory‐phenotype cells retain a subset of accessible chromatin sites as DN ase I‐hypersensitive sites. ETS ‐1 and RUNX 1 remain bound to primed DN ase I‐hypersensitive sites in previously activated T cells. Primed DN ase I‐hypersensitive sites facilitate inducible enhancer function.