CNS2 is a critical regulator of IL-4 production by follicular helper T cells

February 24, 2012 PRESS RELEASE

Upon antigen stimulation, naïve helper T cells differentiate into various types of effector helper T cells. Type 2 helper T (Th2) cells are effector helper T cells that secret the cytokine IL-4 and stimulate B cells to produce IgG1 and IgE antibodies, thus mediating atopic and allergic diseases.

Follicular T (Tfh) cells are a recently defined subset of helper T cells that are distinguishable from other helper T cells in two important ways: by their location in the B cell follicles and by their function - to activate B cells and trigger germinal center formation. This results in clearance of viral and bacterial infections through induction of potent humoral immunity. Like Th2 cells, the Tfh cells also secrete IL-4 and stimulate antibody class switching by B cells to produce IgG1 and IgE antibodies. Differences in the regulatory mechanisms and functions between Th2 and Tfh remained unknown.

To elucidate the mechanisms of IL-4 secretion by Th2 and Tfh cells, Masato Kubo (Open Laboratory for Signal Network) and his team generated a series of mutant mice that genetically lack each cis-acting gene regulatory element in the noncoding regions of theIL-4locus. They found that mice lacking CNS2, an enhancer located ~10 kb downstream of theIL-4coding exons, had a reduced production of IgG1 and IgE. To understand the function of CNS-2, they next generated CNS2 reporter mice, in which CNS2 activated cells could be detected by GFP expression. GFP positive cells were localized in B cell follicles and their gene expression pattern was similar to Tfh cells. From these results, Kubo and the team discovered that CNS2 is the cell type-specificIL-4enhancer in Tfh cells. They also analyzed the development of CNS2-active Tfh cells, and found that these cells developed from naive helper T cells 3-5 days after immunization with antigen.

To test the impact of CNS2-deficiency on allergic diseases, they induced bronchial asthma in CNS-2 deficient mice. Asthma was observed in CNS2 deficient mice, indicating that development of asthmatic disease is mediated by Th2 and not by Tfh cells.

"We revealed a unique role of CNS2 during the induction phase ofIL-4gene expression in the Tfh cell lineage. Tfh cells are important in stimulating B cell antibody production and clearing viral and bacterial infections. Our discovery will be an important step toward the understanding of antibody production and the development of effective vaccines." said Kubo.

(Figure) TFH cells stimulate IgG1 and IgE antibody production