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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Myers, DR; Lau, T; Markegard, E; Lim, HW; Kasler, H; Zhu, M; Barczak, A; Huizar, JP; Zikherman, J; Erle, DJ; Zhang, W; Verdin, E; Roose, JP

Published Date

  • May 23, 2017

Published In

Volume / Issue

  • 19 / 8

Start / End Page

  • 1558 - 1571

PubMed ID

  • 28538176

Pubmed Central ID

  • 28538176

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2017.04.076

Language

  • eng

Conference Location

  • United States