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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.

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(Figure) TFH cells stimulate IgG1 and IgE antibody production