Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells
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
Affiliations
Darienne R. Myers
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA
Tannia Lau
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA
Evan Markegard
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA
Hyung W. Lim
Gladstone Institute of Virology and Immunology, University of California, San Francisco, 1650 Owens Street, San Francisco, CA 94158, USA
Herbert Kasler
Gladstone Institute of Virology and Immunology, University of California, San Francisco, 1650 Owens Street, San Francisco, CA 94158, USA
Minghua Zhu
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
Andrea Barczak
Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
John P. Huizar
Division of Rheumatology, Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
Julie Zikherman
Division of Rheumatology, Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
David J. Erle
Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
Weiguo Zhang
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
Eric Verdin
Gladstone Institute of Virology and Immunology, University of California, San Francisco, 1650 Owens Street, San Francisco, CA 94158, USA
Jeroen P. Roose
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA
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.
