Chromatin Priming Renders T Cell Tolerance-Associated Genes Sensitive to Activation below the Signaling Threshold for Immune Response Genes.

Cell Reports
Sarah L BevingtonPeter N Cockerill

Abstract

Immunological homeostasis in T cells is maintained by a tightly regulated signaling and transcriptional network. Full engagement of effector T cells occurs only when signaling exceeds a critical threshold that enables induction of immune response genes carrying an epigenetic memory of prior activation. Here we investigate the underlying mechanisms causing the suppression of normal immune responses when T cells are rendered anergic by tolerance induction. By performing an integrated analysis of signaling, epigenetic modifications, and gene expression, we demonstrate that immunological tolerance is established when both signaling to and chromatin priming of immune response genes are weakened. In parallel, chromatin priming of immune-repressive genes becomes boosted, rendering them sensitive to low levels of signaling below the threshold needed to activate immune response genes. Our study reveals how repeated exposure to antigens causes an altered epigenetic state leading to T cell anergy and tolerance, representing a basis for treating auto-immune diseases.

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Citations

Feb 3, 2021·Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology·David C Wraith, Mamidipudi T Krishna
Feb 11, 2021·Cell Reports·Anne TrefzerReinhard Obst
Apr 21, 2021·Current Opinion in Immunology·Heather B Streeter, David C Wraith
Aug 3, 2021·Frontiers in Immunology·Sean Robinson, Ranjeny Thomas

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Datasets Mentioned

BETA
GSE147268
GSM1004799
GSM1570758
GSE39756
GSE67443
GSE99319

Methods Mentioned

BETA
PMA
RNA-seq
transgenic
ChIP-seq
ChIP
immunoprecipitation
footprinting
ubiquitination
Confocal microscopy
flow cytometry

Software Mentioned

HOMER package
Treeview
HOMER
annotatePeaks
UCSC
Galaxy
Ensembl
pyDNase
Volocity
DESeq2

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