Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development.
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.
1] Tsinghua University School of Medicine, Beijing 100084, China [2] Department of Immunology, MD Anderson Cancer Center, Houston, Texas 77054, USA.
Xindong
X
Liu
Tsinghua University School of Medicine, Beijing 100084, China.
Xin
X
Chen
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.).
Bo
B
Zhong
1] Tsinghua University School of Medicine, Beijing 100084, China [2] Department of Immunology, MD Anderson Cancer Center, Houston, Texas 77054, USA.
Aibo
A
Wang
1] Tsinghua University School of Medicine, Beijing 100084, China [2] Department of Immunology, MD Anderson Cancer Center, Houston, Texas 77054, USA.
Xiaohu
X
Wang
Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, Texas 77054, USA.
Fuliang
F
Chu
Department of Immunology, MD Anderson Cancer Center, Houston, Texas 77054, USA.
Roza I
RI
Nurieva
Institute for Systems Biology, Seattle, Washington 98103, USA.
Xiaowei
X
Yan
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, Maryland 20892-1858, USA.
Ping
P
Chen
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.).
Laurens G
LG
van der Flier
National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland 20892-2190, USA.
Hiroko
H
Nakatsukasa
Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, Texas 77054, USA.
Sattva S
SS
Neelapu
National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland 20892-2190, USA.
Wanjun
W
Chen
Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
Hans
H
Clevers
Institute for Systems Biology, Seattle, Washington 98103, USA.
Qiang
Q
Tian
Tsinghua University School of Medicine, Beijing 100084, China.
Hai
H
Qi
State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510275, China.
Lai
L
Wei
1] Tsinghua University School of Medicine, Beijing 100084, China [2] Department of Immunology, MD Anderson Cancer Center, Houston, Texas 77054, USA.
Chen
C
Dong
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D018858:Germinal Center / Q000166:cytology* / Q000276:immunology; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D051560:Proto-Oncogene Proteins c-bcl-6; D054400:Receptors, CCR7 / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D015854:Up-Regulation
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D051796:Inhibitor of Differentiation Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D054400:Receptors, CCR7; D054380:Receptors, CXCR5; C065501:ASCL2 protein, human; C489311:Ascl2 protein, mouse; C084103:BCL6 protein, human; C490010:Bcl6 protein, mouse; C095085:CXCR5 protein, human; C513179:CXCR5 protein, mouse; C515371:Ccr7 protein, mouse; C067679:Idb3 protein, mouse