The 3' enhancer CNS2 is a critical regulator of interleukin-4-mediated humoral immunity in follicular helper T cells

Immunity. 2012 Feb 24;36(2):188-200. doi: 10.1016/j.immuni.2012.02.002.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / genetics
  • Cytokines / genetics
  • Enhancer Elements, Genetic*
  • Gene Expression
  • Hypersensitivity / genetics
  • Hypersensitivity / immunology
  • Immunity, Humoral / genetics
  • Immunoglobulin E / biosynthesis
  • Immunoglobulin G / biosynthesis
  • Interleukin-4 / deficiency
  • Interleukin-4 / genetics*
  • Interleukin-4 / immunology*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Sequence Deletion
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocytes, Helper-Inducer / immunology*
  • Th2 Cells / immunology


  • Cytokines
  • Immunoglobulin G
  • Interleukin-4
  • Immunoglobulin E