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.
authors.affiliation: Division of Molecular Pathology, Research Institute for Biological Science, Tokyo University of Science, 2669 Yamazaki, Noda-shi, Chiba, 278-0022, Japan.
authors.forename: Yohsuke
authors.initials: Y
authors.lastname: Harada
authors.forename: Shinya
authors.initials: S
authors.lastname: Tanaka
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Motomura
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Harada
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Ohno
authors.forename: Shinji
authors.initials: S
authors.lastname: Ohno
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yanagi
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Inoue
authors.forename: Masato
authors.initials: M
authors.lastname: Kubo
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D004742:Enhancer Elements, Genetic; D015870:Gene Expression; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology; D056724:Immunity, Humoral / Q000235:genetics; D007073:Immunoglobulin E / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000096:biosynthesis; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017384:Sequence Deletion; D016176:T-Lymphocyte Subsets / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
chemical_list: D016207:Cytokines; D007074:Immunoglobulin G; D015847:Interleukin-4; D007073:Immunoglobulin E