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 journalArticle

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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 Tcells or the induction of the TFH program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation4. Here we show that expression of achaete-scute homologue 2 (Ascl2)-a basic helix-loop-helix (bHLH) transcription factor-is selectively upregulated in T FH 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 T FH-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 T FH-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 T FH-cell development.

Original languageEnglish
Pages (from-to)513-518
Number of pages6
JournalNature
Volume507
Issue number7493
DOIs
Publication statusPublished - 2014 Jan 1
Externally publishedYes

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Helper-Inducer T-Lymphocytes
Transcription Factors
Chemokine Receptors
T-Lymphocytes
CXC Chemokines
Germinal Center
B-Lymphocytes
Basic Helix-Loop-Helix Transcription Factors
CC Chemokines
Th1 Cells
T-Lymphocyte Subsets
Autoimmunity
Genes
Cell Movement
Up-Regulation
Down-Regulation
Genome
Mutation
Antibodies
Proteins

ASJC Scopus subject areas

  • General

Cite this

Liu, X., Chen, X., Zhong, B., Wang, A., Wang, X., Chu, F., ... Dong, C. (2014). Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. Nature, 507(7493), 513-518. https://doi.org/10.1038/nature12910

Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. / Liu, Xindong; Chen, Xin; Zhong, Bo; Wang, Aibo; Wang, Xiaohu; Chu, Fuliang; Nurieva, Roza I.; Yan, Xiaowei; Chen, Ping; Van Der Flier, Laurens G.; Nakatsukasa, Hiroko; Neelapu, Sattva S.; Chen, Wanjun; Clevers, Hans; Tian, Qiang; Qi, Hai; Wei, Lai; Dong, Chen.

In: Nature, Vol. 507, No. 7493, 01.01.2014, p. 513-518.

Research output: Contribution to journalArticle

Liu, X, Chen, X, Zhong, B, Wang, A, Wang, X, Chu, F, Nurieva, RI, Yan, X, Chen, P, Van Der Flier, LG, Nakatsukasa, H, Neelapu, SS, Chen, W, Clevers, H, Tian, Q, Qi, H, Wei, L & Dong, C 2014, 'Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development', Nature, vol. 507, no. 7493, pp. 513-518. https://doi.org/10.1038/nature12910
Liu, Xindong ; Chen, Xin ; Zhong, Bo ; Wang, Aibo ; Wang, Xiaohu ; Chu, Fuliang ; Nurieva, Roza I. ; Yan, Xiaowei ; Chen, Ping ; Van Der Flier, Laurens G. ; Nakatsukasa, Hiroko ; Neelapu, Sattva S. ; Chen, Wanjun ; Clevers, Hans ; Tian, Qiang ; Qi, Hai ; Wei, Lai ; Dong, Chen. / Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. In: Nature. 2014 ; Vol. 507, No. 7493. pp. 513-518.
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AU - Chen, Xin

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AU - Wang, Xiaohu

AU - Chu, Fuliang

AU - Nurieva, Roza I.

AU - Yan, Xiaowei

AU - Chen, Ping

AU - Van Der Flier, Laurens G.

AU - Nakatsukasa, Hiroko

AU - Neelapu, Sattva S.

AU - Chen, Wanjun

AU - Clevers, Hans

AU - Tian, Qiang

AU - Qi, Hai

AU - Wei, Lai

AU - Dong, Chen

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Y1 - 2014/1/1

N2 - 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 Tcells or the induction of the TFH program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation4. Here we show that expression of achaete-scute homologue 2 (Ascl2)-a basic helix-loop-helix (bHLH) transcription factor-is selectively upregulated in T FH 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 T FH-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 T FH-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 T FH-cell development.

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