Publication Date:
2014-01-28
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012617/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012617/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- AI106654/AI/NIAID NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- R01 AI106654/AI/NIAID NIH HHS/ -- R01 AR050772/AR/NIAMS NIH HHS/ -- RC2 AR059010/AR/NIAMS NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2014 Mar 27;507(7493):513-8. doi: 10.1038/nature12910. Epub 2014 Jan 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Tsinghua University School of Medicine, Beijing 100084, China [2] Department of Immunology, MD Anderson Cancer Center, Houston, Texas 77054, USA. ; Tsinghua University School of Medicine, Beijing 100084, China. ; 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.). ; Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, Texas 77054, USA. ; Department of Immunology, MD Anderson Cancer Center, Houston, Texas 77054, USA. ; Institute for Systems Biology, Seattle, Washington 98103, USA. ; Laboratory of Immunology, National Eye Institute, NIH, Bethesda, Maryland 20892-1858, USA. ; 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.). ; National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland 20892-2190, USA. ; Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands. ; State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510275, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24463518" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Basic Helix-Loop-Helix Transcription Factors/antagonists &
;
inhibitors/deficiency/genetics/*metabolism
;
*Cell Differentiation/genetics
;
Cell Movement
;
DNA-Binding Proteins/metabolism
;
Down-Regulation
;
Germinal Center/*cytology/immunology
;
Humans
;
Inhibitor of Differentiation Proteins/genetics/metabolism
;
Mice
;
Mutation/genetics
;
Receptors, CCR7/metabolism
;
Receptors, CXCR5/metabolism
;
T-Lymphocytes, Helper-Inducer/*cytology/immunology/*metabolism
;
Th17 Cells/cytology/immunology/metabolism
;
Transcription, Genetic/genetics
;
Up-Regulation
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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