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

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          Abstract

          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.

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          Author and article information

          Journal
          Cell Rep
          Cell reports
          Elsevier BV
          2211-1247
          May 23 2017
          : 19
          : 8
          Affiliations
          [1 ] Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
          [2 ] Gladstone Institute of Virology and Immunology, University of California, San Francisco, 1650 Owens Street, San Francisco, CA 94158, USA.
          [3 ] Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
          [4 ] Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
          [5 ] 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.
          [6 ] Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: jeroen.roose@ucsf.edu.
          Article
          S2211-1247(17)30605-8
          10.1016/j.celrep.2017.04.076
          28538176

          Nur77, tonic signals, gene expression, Th2, T cells, LAT, Irf4, HDAC

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