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

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78 Citations (Scopus)


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 languageEnglish
Pages (from-to)188-200
Number of pages13
Issue number2
Publication statusPublished - Feb 24 2012


All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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