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

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Darienne R. Myers, Tannia Lau, Evan Markegard, Hyung W. Lim, Herbert Kasler, Minghua Zhu, Andrea Barczak, John P. Huizar, Julie Zikherman, David J. Erle, Weiguo Zhang, Eric Verdin, Jeroen P. Roose
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.

Graphical abstract

Teaser

Myers et al. find that tonic signals through the adaptor LAT are critical to maintain naive T cell homeostasis. They delineate a tonic LAT-PLCγ-HDAC7 pathway that controls expression of HDAC7 targets. Disruption of the pathway leads to reduced expression of targets Nur77 and Irf4 and aberrant lymphocyte proliferation and differentiation.


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