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Abstract

Success of most current vaccines relies on the production of high-affinity antibodies. The generation of high-affinity antibody producing B cells occurs within the germinal center, and CD4+ T follicular helper cells (Tfh) play an indispensable role during the maturation of these B cells. A critical step in this process is the secretion of interleukin-4 (IL-4) by Tfh cells. IL-4 signaling in germinal center B cells is required for affinity maturation of IgG1. IL-4 production by Tfh cells appears to occur independently from the classical Th2 differentiation pathway. Currently, the mechanisms regulating IL-4 production by Tfh cells are unknown. One intriguing possibility for non-canonical IL-4 production in Tfh cells is the Notch pathway. Notch signaling is required for the differentiation of Tfh cells, and has been shown to modulate IL-4 production. Here, we provide mechanistic evidence for Notch signaling in the production of IL-4 by Tfh cells. Inhibition of Notch signaling after germinal center formation resulted in a significant decrease in the percentage and number of Tfh cells actively producing IL-4. Furthermore, inhibition of Notch signaling led to decreased expression of the chemokine receptor CXCR5 in IL-4 producing CD4+ T cells, which corresponded to a repositioning of IL-4-competent cells outside of the germinal center. These findings suggest a model in which Notch signaling is not only important in Tfh differentiation, but also in Tfh function and maintenance.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://dbpia.nl.go.kr/pages/standard-publication-reuse-rights)
Issue Section:
Immune Regulation by Cytokines and Chemokines Session
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