CD4-CD8 lineage commitment is regulated by a silencer element at the ThPOK transcription-factor locus

Immunity. 2008 Mar;28(3):346-58. doi: 10.1016/j.immuni.2008.02.006.


The transcription factor ThPOK is necessary and sufficient to trigger adoption of the CD4 lymphocyte fate. Here we investigate the regulation of ThPOK expression and its subsequent control of CD4+ T cell commitment. Treatment of immature thymocytes with anti-TCR (T cell receptor) showed that TCR signals were important in ThPOK induction and that the CD4+8lo stage was the likely target of the inductive TCR signal. We identified at the ThPOK locus a key distal regulatory element (DRE) that mediated its differential expression in class I- versus II-restricted CD4+8lo thymocytes. The DRE was both necessary for suppression of ThPOK expression in class I-restricted thymocytes and sufficient for its induction in class II-restricted thymocytes. Mutagenesis analysis defined an essential 80bp core DRE sequence and its potential regulatory motifs. We propose a silencer-dependent model of lineage choice, whereby inactivation of the DRE silencer by a strong TCR signal leads to CD4 commitment, whereas continued silencer activity leads to CD8 commitment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology*
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Differentiation / immunology
  • Cell Lineage / genetics*
  • Cell Lineage / immunology
  • Flow Cytometry
  • Gene Expression Regulation*
  • Mice
  • Mice, Transgenic
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Silencer Elements, Transcriptional / genetics*
  • Silencer Elements, Transcriptional / immunology
  • Thymus Gland / cytology
  • Thymus Gland / immunology
  • Transcription Factors / genetics*
  • Transcription Factors / immunology


  • Receptors, Antigen, T-Cell
  • Th-POK protein, mouse
  • Transcription Factors