Darienne R Myers 1 , Tannia Lau 1 , Evan Markegard 1 , Hyung W Lim 2 , Herbert Kasler 2 , Minghua Zhu 3 , Andrea Barczak 4 , John P Huizar 5 , Julie Zikherman 5 , David J Erle 4 , Weiguo Zhang 3 , Eric Verdin 2 , Jeroen P Roose 6
May 23 2017
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 (TH2) 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 TH2 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.