Format

Send to

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

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

Author information

1
1] Tsinghua University School of Medicine, Beijing 100084, China [2] Department of Immunology, MD Anderson Cancer Center, Houston, Texas 77054, USA.
2
Tsinghua University School of Medicine, Beijing 100084, China.
3
1] Department of Immunology, MD Anderson Cancer Center, Houston, Texas 77054, USA [2] College of Life Sciences, Wuhan University, Wuhan 430072, China (B.Z.); SomantiX B.V., Padualaan 8, 3584 CH Utrecht, the Netherlands (L.G.v.d.F.).
4
Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, Texas 77054, USA.
5
Department of Immunology, MD Anderson Cancer Center, Houston, Texas 77054, USA.
6
Institute for Systems Biology, Seattle, Washington 98103, USA.
7
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, Maryland 20892-1858, USA.
8
1] Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands [2] College of Life Sciences, Wuhan University, Wuhan 430072, China (B.Z.); SomantiX B.V., Padualaan 8, 3584 CH Utrecht, the Netherlands (L.G.v.d.F.).
9
National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland 20892-2190, USA.
10
Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
11
State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510275, China.

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.

PMID:
24463518
PMCID:
PMC4012617
DOI:
10.1038/nature12910
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Secondary source ID, Grant support

Publication types

MeSH terms

Substances

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center