T Cell Receptor and Cytokine Signaling Can Function at Different Stages to Establish and Maintain Transcriptional Memory and Enable T Helper Cell Differentiation.

Sarah L Bevington,Pierre Cauchy,Peter J L Lane,Peter N Cockerill,David R Withers

doi:10.3389/fimmu.2017.00204

Sarah L Bevington, Pierre Cauchy + Show 3 more

Open Access

https://doi.org/10.3389/fimmu.2017.00204

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Abstract

Experienced T cells exhibit immunological memory via a rapid recall response, responding to restimulation much faster than naïve T cells. The formation of immunological memory starts during an initial slow response, when naïve T cells become transformed to proliferating T blast cells, and inducible immune response genes are reprogrammed as active chromatin domains. We demonstrated that these active domains are supported by thousands of priming elements which cooperate with inducible transcriptional enhancers to enable efficient responses to stimuli. At the conclusion of this response, a small proportion of these cells return to the quiescent state as long-term memory T cells. We proposed that priming elements can be established in a hit-and-run process dependent on the inducible factor AP-1, but then maintained by the constitutive factors RUNX1 and ETS-1. This priming mechanism may also function to render genes receptive to additional differentiation-inducing factors such as GATA3 and TBX21 that are encountered under polarizing conditions. The proliferation of recently activated T cells and the maintenance of immunological memory in quiescent memory T cells are also dependent on various cytokine signaling pathways upstream of AP-1. We suggest that immunological memory is established by T cell receptor signaling, but maintained by cytokine signaling.

Highlights

The adaptive immune system relies on both specific antigen (Ag) recognition and on the ability of lymphocytes to maintain a memory of previous encounters with Ags
Activation of the T cell receptor (TCR) triggers a hit-and-run mechanism whereby a single cycle of activation leads to the acquisition of thousands of stably maintained active chromatin regions which include many of the inducible immune response genes that deliver effective immune responses [10]
By identifying all of the DNase I hypersensitive sites (DHSs) that are present in recently activated murine CD4 T blast cells and CD4 memory T cells, but not in naïve CD4 T cells, we identified ~3,000 newly acquired and stably maintained primed DHSs that could potentially account for immunological memory in T cells (Figures 3A,B) [10]

Summary

INTRODUCTION

The adaptive immune system relies on both specific antigen (Ag) recognition and on the ability of lymphocytes to maintain a memory of previous encounters with Ags. The process of T blast cell transformation, which is required to make the rapid recall response possible, involves extensive chromatin remodeling, whereby the Brg SWI/ SNF family chromatin remodeling complex mediates epigenetic reprogramming of the genome to prime inducible loci for transcriptional reactivation [24] This hit-and-run mechanism, triggered by TCR signaling, establishes thousands of open chromatin regions embedded within extensive active chromatin domains [10, 18]. By identifying all of the DHSs that are present in recently activated murine CD4 T blast cells and CD4 memory T cells, but not in naïve CD4 T cells, we identified ~3,000 newly acquired and stably maintained primed DHSs (pDHSs) that could potentially account for immunological memory in T cells (Figures 3A,B) [10] These DHSs fulfilled some of the essential features needed for a priming mechanism, because they supported the maintenance of domains of active chromatin modified by H3K4me and H3K27ac without having any significant impact on steady-state levels of transcription [10, 18] (Figure 3B). The most highly inducible genes were found to be the loci where pDHSs and iDHSs were the closest, independently of their distance from the inducible promoters that they controlled

A HIT-AND-RUN MODEL OF IMMUNOLOGICAL MEMORY IN T CELLS

Findings

CONCLUDING STATEMENT