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

Xindong Liu, Xin Chen, Bo Zhong, Aibo Wang, Xiaohu Wang, Fuliang Chu, Roza I Nurieva, Xiaowei Yan, Ping Chen, Laurens G van der Flier, Hiroko Nakatsukasa, Sattva S Neelapu, Wanjun Chen, Hans Clevers, Qiang Tian, Hai Qi, Lai Wei, Chen Dong

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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.

Original languageEnglish
Pages (from-to)513-8
Number of pages6
JournalNature
Volume507
Issue number7493
DOIs
Publication statusPublished - 27 Mar 2014

Keywords

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Differentiation
  • Cell Movement
  • DNA-Binding Proteins
  • Down-Regulation
  • Germinal Center
  • Humans
  • Inhibitor of Differentiation Proteins
  • Mice
  • Mutation
  • Receptors, CCR7
  • Receptors, CXCR5
  • T-Lymphocytes, Helper-Inducer
  • Th17 Cells
  • Transcription, Genetic
  • Up-Regulation

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