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

doi:10.1038/nature12910

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

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

277 Citations (Scopus)

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 language	English
Pages (from-to)	513-8
Number of pages	6
Journal	Nature
Volume	507
Issue number	7493
DOIs	https://doi.org/10.1038/nature12910
Publication status	Published - 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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10.1038/nature12910

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Liu, X., Chen, X., Zhong, B., Wang, A., Wang, X., Chu, F., Nurieva, R. I., Yan, X., Chen, P., van der Flier, L. G., Nakatsukasa, H., Neelapu, S. S., 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, 507(7493), 513-8. https://doi.org/10.1038/nature12910

@article{56e5e1b6e5b24fabb740060c8a970b43,

title = "Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development",

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.",

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

year = "2014",

month = mar,

day = "27",

doi = "10.1038/nature12910",

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TY - JOUR

T1 - Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development

AU - Liu, Xindong

AU - Chen, Xin

AU - Zhong, Bo

AU - Wang, Aibo

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

PY - 2014/3/27

Y1 - 2014/3/27

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 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.

AB - 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.

KW - Animals

KW - Basic Helix-Loop-Helix Transcription Factors

KW - Cell Differentiation

KW - Cell Movement

KW - DNA-Binding Proteins

KW - Down-Regulation

KW - Germinal Center

KW - Humans

KW - Inhibitor of Differentiation Proteins

KW - Mice

KW - Mutation

KW - Receptors, CCR7

KW - Receptors, CXCR5

KW - T-Lymphocytes, Helper-Inducer

KW - Th17 Cells

KW - Transcription, Genetic

KW - Up-Regulation

U2 - 10.1038/nature12910

DO - 10.1038/nature12910

M3 - Article

C2 - 24463518

SN - 0028-0836

VL - 507

SP - 513

EP - 518

JO - Nature

JF - Nature

IS - 7493

ER -

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

Abstract

Keywords

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