Bcl11b, a Novel GATA3-interacting Protein, Suppresses Th1 While Limiting Th2 Cell Differentiation

J Exp Med. 2018 May 7;215(5):1449-1462. doi: 10.1084/jem.20171127. Epub 2018 Mar 7.

Abstract

GATA-binding protein 3 (GATA3) acts as the master transcription factor for type 2 T helper (Th2) cell differentiation and function. However, it is still elusive how GATA3 function is precisely regulated in Th2 cells. Here, we show that the transcription factor B cell lymphoma 11b (Bcl11b), a previously unknown component of GATA3 transcriptional complex, is involved in GATA3-mediated gene regulation. Bcl11b binds to GATA3 through protein-protein interaction, and they colocalize at many important cis-regulatory elements in Th2 cells. The expression of type 2 cytokines, including IL-4, IL-5, and IL-13, is up-regulated in Bcl11b-deficient Th2 cells both in vitro and in vivo; such up-regulation is completely GATA3 dependent. Genome-wide analyses of Bcl11b- and GATA3-regulated genes (from RNA sequencing), cobinding patterns (from chromatin immunoprecipitation sequencing), and Bcl11b-modulated epigenetic modification and gene accessibility suggest that GATA3/Bcl11b complex is involved in limiting Th2 gene expression, as well as in inhibiting non-Th2 gene expression. Thus, Bcl11b controls both GATA3-mediated gene activation and repression in Th2 cells.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Cell Differentiation*
  • Cell Proliferation
  • Chromatin / metabolism
  • Cytokines / metabolism
  • Epigenesis, Genetic
  • GATA3 Transcription Factor / metabolism*
  • Genome
  • Lectins, C-Type / metabolism
  • Mice, Inbred C57BL
  • Protein Binding
  • Repressor Proteins / metabolism*
  • Th1 Cells / cytology*
  • Th2 Cells / cytology*
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • Bcl11b protein, mouse
  • CD69 antigen
  • Chromatin
  • Cytokines
  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • Lectins, C-Type
  • Repressor Proteins
  • Tumor Suppressor Proteins