Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells

Abstract

CD4⁺ T cells differentiate into T helper cell subsets in feedforward manners with synergistic signals from the T cell receptor (TCR), cytokines, and lineage-specific transcription factors. Naive CD4⁺ T cells avoid spontaneous engagement of feedforward mechanisms but retain a prepared state. T cells lacking the adaptor molecule LAT demonstrate impaired TCR-induced signals yet cause a spontaneous lymphoproliferative T helper 2 (T_H2) cell syndrome in mice. Thus, LAT constitutes an unexplained maintenance cue. Here, we demonstrate that tonic signals through LAT constitutively export the repressor HDAC7 from the nucleus of CD4⁺ T cells. Without such tonic signals, HDAC7 target genes Nur77 and Irf4 are repressed. We reveal that Nur77 suppresses CD4⁺ T cell proliferation and uncover a suppressive role for Irf4 in T_H2 polarization; halving Irf4 gene-dosage leads to increases in GATA3⁺ and IL-4⁺ cells. Our studies reveal that naive CD4⁺ T cells are dynamically tuned by tonic LAT-HDAC7 signals.

Keywords: HDAC; Irf4; LAT; Nur77; T cells; Th2; gene expression; tonic signals.