Quality of TCR signaling determined by differential affinities of enhancers for the composite BATF-IRF4 transcription factor complex.

Abstract:

:Variable strengths of signaling via the T cell antigen receptor (TCR) can produce divergent outcomes, but the mechanism of this remains obscure. The abundance of the transcription factor IRF4 increases with TCR signal strength, but how this would induce distinct types of responses is unclear. We compared the expression of genes in the TH2 subset of helper T cells to enhancer occupancy by the BATF-IRF4 transcription factor complex at varying strengths of TCR stimulation. Genes dependent on BATF-IRF4 clustered into groups with distinct TCR sensitivities. Enhancers exhibited a spectrum of occupancy by the BATF-IRF4 ternary complex that correlated with the sensitivity of gene expression to TCR signal strength. DNA sequences immediately flanking the previously defined AICE motif controlled the affinity of BATF-IRF4 for direct binding to DNA. Analysis by the chromatin immunoprecipitation-exonuclease (ChIP-exo) method allowed the identification of a previously unknown high-affinity AICE2 motif at a human single-nucleotide polymorphism (SNP) of the gene encoding the immunomodulatory receptor CTLA-4 that was associated with resistance to autoimmunity. Thus, the affinity of different enhancers for the BATF-IRF4 complex might underlie divergent signaling outcomes in response to various strengths of TCR signaling.

journal_name

Nat Immunol

journal_title

Nature immunology

authors

Iwata A,Durai V,Tussiwand R,Briseño CG,Wu X,Grajales-Reyes GE,Egawa T,Murphy TL,Murphy KM

doi

10.1038/ni.3714

subject

Has Abstract

pub_date

2017-05-01 00:00:00

pages

563-572

issue

5

eissn

1529-2908

issn

1529-2916

pii

ni.3714

journal_volume

18

pub_type

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