Immunity
Volume 46, Issue 1, 17 January 2017, Pages 65-77
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Article
Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification

https://doi.org/10.1016/j.immuni.2016.11.006Get rights and content
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Highlights

  • Two functional isoforms of the E protein factor TCF4 (E2-2) are expressed in pDCs

  • The “long” TCF4 isoform is pDC specific and controls pDC development in vivo

  • A conserved enhancer controls TCF4 expression and pDC development

  • TCF4 expression and pDC development are sensitive to BET protein inhibitors

Summary

The cell fate decision between interferon-producing plasmacytoid DC (pDC) and antigen-presenting classical DC (cDC) is controlled by the E protein transcription factor TCF4 (E2-2). We report that TCF4 comprises two transcriptional isoforms, both of which are required for optimal pDC development in vitro. The long Tcf4 isoform is expressed specifically in pDCs, and its deletion in mice impaired pDCs development and led to the expansion of non-canonical CD8+ cDCs. The expression of Tcf4 commenced in progenitors and was further upregulated in pDCs, correlating with stage-specific activity of multiple enhancer elements. A conserved enhancer downstream of Tcf4 was required for its upregulation during pDC differentiation, revealing a positive feedback loop. The expression of Tcf4 and the resulting pDC differentiation were selectively sensitive to the inhibition of enhancer-binding BET protein activity. Thus, lineage-specifying function of E proteins is facilitated by lineage-specific isoform expression and by BET-dependent feedback regulation through distal regulatory elements.

Keywords

dendritic cells
plasmacytoid dendritic cells
transcription factors
E proteins
enhancers
feedback regulation

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