The 3′ Enhancer CNS2 Is a Critical Regulator of Interleukin-4-Mediated Humoral Immunity in Follicular Helper T Cells

SummaryA 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.

Graphical AbstractFigure optionsDownload high-quality image (168 K)Download as PowerPoint slideHighlights
► CNS2 is a critical enhancer for IL-4-expressing Tfh cells
► IL-4-expressing Tfh cells are distinct from Th2 cells
► CNS2 is essential for IL-4-dependent antibody responses
► Tfh cells can be directly developed from naive T cells with antigen priming