The 3' Enhancer CNS2 Is a Critical Regulator of Interleukin-4-Mediated Humoral Immunity in Follicular Helper T Cells

Yohsuke Harada; Shinya Tanaka; Yasutaka Motomura; Yasuyo Harada; Shin Ichiro Ohno; Shinji Ohno; Yusuke Yanagi; Hiromasa Inoue; Masato Kubo

doi:10.1016/j.immuni.2012.02.002

The 3' Enhancer CNS2 Is a Critical Regulator of Interleukin-4-Mediated Humoral Immunity in Follicular Helper T Cells

Yohsuke Harada, Shinya Tanaka, Yasutaka Motomura, Yasuyo Harada, Shin Ichiro Ohno, Shinji Ohno, Yusuke Yanagi, Hiromasa Inoue, Masato Kubo

Department of Basic Medicine

Research output: Contribution to journal › Article › peer-review

109 Citations (Scopus)

Abstract

A main role for interleukin-4 (IL-4) is in humoral immunity, and follicular helper CD4 ⁺ T (Tfh) cells may be an intrinsic IL-4 source. Here we demonstrate that conserved noncoding sequence 2 (CNS2) is an essential enhancer element for IL-4 expression in Tfh cells but not in Th2 cells. Mice with a CNS2 deletion had a reduction in IgG1 and IgE production and in IL-4 expression in Tfh cells. Tracking of CNS2 activity via a GFP reporter mouse demonstrated that CNS2-active cells expressed several markers of Tfh cells: CXCR5, PD-1, and ICOS; the transcriptional master regulator Bcl6; and the cytokines IL-21 and IL-4. These CNS2-active cells were mainly localized in B cell follicles and germinal centers. The GFP ⁺ Tfh cells were derived from GFP ^- naive T cells after in vivo systemic immunization. These results indicate that CNS2 is an essential enhancer element required for IL-4 expression in Tfh cells controlling humoral immunity.

Original language	English
Pages (from-to)	188-200
Number of pages	13
Journal	Immunity
Volume	36
Issue number	2
DOIs	https://doi.org/10.1016/j.immuni.2012.02.002
Publication status	Published - Feb 24 2012

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology
Infectious Diseases

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2012.02.002

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title = "The 3' Enhancer CNS2 Is a Critical Regulator of Interleukin-4-Mediated Humoral Immunity in Follicular Helper T Cells",

abstract = "A main role for interleukin-4 (IL-4) is in humoral immunity, and follicular helper CD4 + T (Tfh) cells may be an intrinsic IL-4 source. Here we demonstrate that conserved noncoding sequence 2 (CNS2) is an essential enhancer element for IL-4 expression in Tfh cells but not in Th2 cells. Mice with a CNS2 deletion had a reduction in IgG1 and IgE production and in IL-4 expression in Tfh cells. Tracking of CNS2 activity via a GFP reporter mouse demonstrated that CNS2-active cells expressed several markers of Tfh cells: CXCR5, PD-1, and ICOS; the transcriptional master regulator Bcl6; and the cytokines IL-21 and IL-4. These CNS2-active cells were mainly localized in B cell follicles and germinal centers. The GFP + Tfh cells were derived from GFP - naive T cells after in vivo systemic immunization. These results indicate that CNS2 is an essential enhancer element required for IL-4 expression in Tfh cells controlling humoral immunity.",

author = "Yohsuke Harada and Shinya Tanaka and Yasutaka Motomura and Yasuyo Harada and Ohno, {Shin Ichiro} and Shinji Ohno and Yusuke Yanagi and Hiromasa Inoue and Masato Kubo",

note = "Funding Information: We thank H. Fujimoto, Y. Hachiman, Y. Suzuki, and K. Ikari for technical support and animal maintenance. We thank P. Burrows for helpful comments on the manuscript. This work was supported by a Grant-in-Aid-of-Scientific Research in Priority Areas of the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan and the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) and Takeda foundation. Y.M. is a recipient of Research Associate grant at TUS. ",

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AU - Harada, Yohsuke

AU - Tanaka, Shinya

AU - Motomura, Yasutaka

AU - Harada, Yasuyo

AU - Ohno, Shin Ichiro

AU - Ohno, Shinji

AU - Yanagi, Yusuke

AU - Inoue, Hiromasa

AU - Kubo, Masato

N1 - Funding Information: We thank H. Fujimoto, Y. Hachiman, Y. Suzuki, and K. Ikari for technical support and animal maintenance. We thank P. Burrows for helpful comments on the manuscript. This work was supported by a Grant-in-Aid-of-Scientific Research in Priority Areas of the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan and the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) and Takeda foundation. Y.M. is a recipient of Research Associate grant at TUS.

PY - 2012/2/24

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N2 - A main role for interleukin-4 (IL-4) is in humoral immunity, and follicular helper CD4 + T (Tfh) cells may be an intrinsic IL-4 source. Here we demonstrate that conserved noncoding sequence 2 (CNS2) is an essential enhancer element for IL-4 expression in Tfh cells but not in Th2 cells. Mice with a CNS2 deletion had a reduction in IgG1 and IgE production and in IL-4 expression in Tfh cells. Tracking of CNS2 activity via a GFP reporter mouse demonstrated that CNS2-active cells expressed several markers of Tfh cells: CXCR5, PD-1, and ICOS; the transcriptional master regulator Bcl6; and the cytokines IL-21 and IL-4. These CNS2-active cells were mainly localized in B cell follicles and germinal centers. The GFP + Tfh cells were derived from GFP - naive T cells after in vivo systemic immunization. These results indicate that CNS2 is an essential enhancer element required for IL-4 expression in Tfh cells controlling humoral immunity.

AB - A main role for interleukin-4 (IL-4) is in humoral immunity, and follicular helper CD4 + T (Tfh) cells may be an intrinsic IL-4 source. Here we demonstrate that conserved noncoding sequence 2 (CNS2) is an essential enhancer element for IL-4 expression in Tfh cells but not in Th2 cells. Mice with a CNS2 deletion had a reduction in IgG1 and IgE production and in IL-4 expression in Tfh cells. Tracking of CNS2 activity via a GFP reporter mouse demonstrated that CNS2-active cells expressed several markers of Tfh cells: CXCR5, PD-1, and ICOS; the transcriptional master regulator Bcl6; and the cytokines IL-21 and IL-4. These CNS2-active cells were mainly localized in B cell follicles and germinal centers. The GFP + Tfh cells were derived from GFP - naive T cells after in vivo systemic immunization. These results indicate that CNS2 is an essential enhancer element required for IL-4 expression in Tfh cells controlling humoral immunity.

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The 3' Enhancer CNS2 Is a Critical Regulator of Interleukin-4-Mediated Humoral Immunity in Follicular Helper T Cells

Abstract

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