Tonic LAT-HDAC7 signals sustain Nur77 and Irf4 expression to tune naïve CD4 T cells

Summary

CD4 ⁺ T cells differentiate into T helper cell subsets in feed-forward manners with synergistic signals from the T cell receptor (TCR), cytokines, and lineage-specific transcription factors. Naïve CD4 ⁺ T cells avoid spontaneous engagement of feed-forward mechanisms but retain a prepared state. T cells lacking the adapter 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 IL4+ cells. Our studies reveal that naïve CD4 ⁺ T cells are dynamically tuned by tonic LAT-HDAC7 signals.

Graphical abstract