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

Abstract

Variable strengths of T cell receptor (TCR) signaling can produce divergent outcomes, but the mechanism 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 TH2 gene expression with BATF/IRF4 enhancer occupancy at varying strengths of TCR stimulation. BATF/IRF4-dependent genes clustered into distinct TCR-sensitivities. Enhancers exhibited a spectrum of occupancy by BATF/IRF4 ternary complex that correlated with TCR-sensitivity of gene expression. DNA sequences immediately flanking the previously defined AICE motif controlled the affinity for BATF/IRF4 for direct binding to DNA. ChIP-exo analysis allowed identification of a novel high-affinity AICE2 motif at a human SNP of CTLA4 associated with resistance to autoimmunity. Thus, the affinity of different enhancers for the BATF-IRF4 complex may underlie divergent signaling outcomes in response to various strengths of TCR signaling.