Bcl11b is essential for licensing Th2 differentiation during helminth infection and allergic asthma

Nat Commun. 2018 Apr 26;9(1):1679. doi: 10.1038/s41467-018-04111-0.

Abstract

During helminth infection and allergic asthma, naive CD4+ T-cells differentiate into cytokine-producing Type-2 helper (Th2) cells that resolve the infection or induce asthma-associated pathology. Mechanisms regulating the Th2 differentiation in vivo remain poorly understood. Here we report that mice lacking Bcl11b in mature T-cells have a diminished capacity to mount Th2 responses during helminth infection and allergic asthma, showing reduced Th2 cytokines and Gata3, and elevated Runx3. We provide evidence that Bcl11b is required to maintain chromatin accessibility at Th2-cytokine promoters and locus-control regions, and binds the Il4 HS IV silencer, reducing its accessibility. Bcl11b also binds Gata3-intronic and downstream-noncoding sites, sustaining the Gata3 expression. In addition, Bcl11b binds and deactivates upstream enhancers at Runx3 locus, restricting the Runx3 expression and its availability to act at the Il4 HS IV silencer. Thus, our results establish novel roles for Bcl11b in the regulatory loop that licenses Th2 program in vivo.

Publication types

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

MeSH terms

  • Animals
  • Asthma / genetics
  • Asthma / immunology
  • Asthma / physiopathology*
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Differentiation
  • Female
  • GATA3 Transcription Factor / genetics
  • GATA3 Transcription Factor / immunology
  • Helminthiasis / genetics
  • Helminthiasis / immunology
  • Helminthiasis / parasitology
  • Helminthiasis / physiopathology*
  • Helminths / physiology
  • Humans
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology
  • Male
  • Mice
  • Mice, Knockout
  • Repressor Proteins / genetics*
  • Repressor Proteins / immunology
  • Th2 Cells / cytology*
  • Th2 Cells / immunology
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / immunology

Substances

  • Bcl11b protein, mouse
  • GATA3 Transcription Factor
  • Repressor Proteins
  • Tumor Suppressor Proteins
  • Interleukin-4