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.

B Cell–Intrinsic MyD88 Signaling Is Essential for IgE Responses in Lungs Exposed to Pollen Allergens

“…However, recent advances revealed that Tfh cells, rather than Th2 cells or other Th subsets, are important for controlling humoral immunity (43). In addition, previous studies reported the differential regulation of Th2 cell development and Tfh cell-controlled IgE production (43,44). In the current study, Tfh cell development was abrogated in Myd88 2/2 mice with ragweed pollen exposure in the lung.…”

“…In classical immunology, it was thought that Th2 cells and IgE production should occur concurrently. However, recent advances revealed that Tfh cells, rather than Th2 cells or other Th subsets, are important for controlling humoral immunity (43). In addition, previous studies reported the differential regulation of Th2 cell development and Tfh cell-controlled IgE production (43,44).…”

Notch Signaling Regulates Follicular Helper T Cell Differentiation

“…Of note, in these studies, only IL-4 and its related isotype switching were measured as a readout for Th2 cell differentiation. Activation of IL-4 in T FH cells was recently shown to be mainly dependent on a conserved IL-4 enhancer (CNS2) (26,27), and Notch intracellular domain was previously shown to bind selectively to CNS2 in a reporter assay (17,18,28). Only very few T FH cells developed in N1N2…”

A distinct subpopulation of CD25−T-follicular regulatory cells localizes in the germinal centers

“…All experiments used mice on a C57BL/6 background except where noted. BCL6 flox, IL-2 −/− , BLIMP-1 reporter, Foxp3 fusion protein DTR-GFP (FDG), Foxp3-Gfp eFox, and IL-21 reporter mice have already been described (45)(46)(47)(48)(49).…”