Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development

Nature. 2014 Mar 27;507(7493):513-8. doi: 10.1038/nature12910. Epub 2014 Jan 19.

Abstract

In immune responses, activated T cells migrate to B-cell follicles and develop into follicular T-helper (TFH) cells, a recently identified subset of CD4(+) T cells specialized in providing help to B lymphocytes in the induction of germinal centres. Although Bcl6 has been shown to be essential in TFH-cell function, it may not regulate the initial migration of T cells or the induction of the TFH program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation. Here we show that expression of achaete-scute homologue 2 (Ascl2)--a basic helix-loop-helix (bHLH) transcription factor--is selectively upregulated in TFH cells. Ectopic expression of Ascl2 upregulates CXCR5 but not Bcl6, and downregulates C-C chemokine receptor 7 (CCR7) expression in T cells in vitro, as well as accelerating T-cell migration to the follicles and TFH-cell development in vivo in mice. Genome-wide analysis indicates that Ascl2 directly regulates TFH-related genes whereas it inhibits expression of T-helper cell 1 (TH1) and TH17 signature genes. Acute deletion of Ascl2, as well as blockade of its function with the Id3 protein in CD4(+) T cells, results in impaired TFH-cell development and germinal centre response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances TFH-cell generation. Thus, Ascl2 directly initiates TFH-cell development.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors
  • Basic Helix-Loop-Helix Transcription Factors / deficiency
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Differentiation* / genetics
  • Cell Movement
  • DNA-Binding Proteins / metabolism
  • Down-Regulation
  • Germinal Center / cytology*
  • Germinal Center / immunology
  • Humans
  • Inhibitor of Differentiation Proteins / genetics
  • Inhibitor of Differentiation Proteins / metabolism
  • Mice
  • Mutation / genetics
  • Proto-Oncogene Proteins c-bcl-6
  • Receptors, CCR7 / metabolism
  • Receptors, CXCR5 / metabolism
  • T-Lymphocytes, Helper-Inducer / cytology*
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / metabolism*
  • Th17 Cells / cytology
  • Th17 Cells / immunology
  • Th17 Cells / metabolism
  • Transcription, Genetic / genetics
  • Up-Regulation

Substances

  • ASCL2 protein, human
  • Ascl2 protein, mouse
  • BCL6 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Bcl6 protein, mouse
  • CXCR5 protein, human
  • CXCR5 protein, mouse
  • Ccr7 protein, mouse
  • DNA-Binding Proteins
  • Inhibitor of Differentiation Proteins
  • Proto-Oncogene Proteins c-bcl-6
  • Receptors, CCR7
  • Receptors, CXCR5
  • Idb3 protein, mouse

Associated data

  • GEO/GSE52840