IL-2 imprints human naive B cell fate towards plasma cell through ERK/ELK1-mediated BACH2 repression

Nat Commun. 2017 Nov 13;8(1):1443. doi: 10.1038/s41467-017-01475-7.

Abstract

Plasma cell differentiation is a tightly regulated process that requires appropriate T cell helps to reach the induction threshold. To further understand mechanisms by which T cell inputs regulate B cell fate decision, we investigate the minimal IL-2 stimulation for triggering human plasma cell differentiation in vitro. Here we show that the timed repression of BACH2 through IL-2-mediated ERK/ELK1 signalling pathway directs plasma cell lineage commitment. Enforced BACH2 repression in activated B cells unlocks the plasma cell transcriptional program and induces their differentiation into immunoglobulin M-secreting cells. RNA-seq and ChIP-seq results further identify BACH2 target genes involved in this process. An active regulatory region within the BACH2 super-enhancer, under ELK1 control and differentially regulated upon B-cell activation and cellular divisions, helps integrate IL-2 signal. Our study thus provides insights into the temporal regulation of BACH2 and its targets for controlling the differentiation of human naive B cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic-Leucine Zipper Transcription Factors / antagonists & inhibitors*
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Cell Differentiation / immunology*
  • Cells, Cultured
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Gene Regulatory Networks / immunology
  • Humans
  • Immunoglobulin M / biosynthesis
  • Immunoglobulin M / immunology
  • Interleukin-2 / immunology*
  • Lymphocyte Activation / immunology
  • Plasma Cells / cytology*
  • Plasma Cells / immunology
  • Positive Regulatory Domain I-Binding Factor 1 / biosynthesis
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology
  • X-Box Binding Protein 1 / biosynthesis
  • ets-Domain Protein Elk-1 / metabolism*

Substances

  • BACH2 protein, human
  • Basic-Leucine Zipper Transcription Factors
  • ELK1 protein, human
  • IL2 protein, human
  • Immunoglobulin M
  • Interleukin-2
  • RNA, Small Interfering
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • ets-Domain Protein Elk-1
  • PRDM1 protein, human
  • Positive Regulatory Domain I-Binding Factor 1
  • Extracellular Signal-Regulated MAP Kinases