Notch signaling is required for the generation and function of follicular T helper cells in settings of Type-2 inflammation.

Abstract

Abstract The presence of IgE and IgG1 antibodies are hallmarks of allergic responses. The generation of high affinity, class-switched antibodies is reliant on interactions of B cells with T follicular helper (Tfh) cells in germinal centers. IL-4 produced by Tfh cells plays a critical role in B cell maturation and survival. The mechanisms controlling IL-4 production by Tfh cells remain largely unknown. Given that Notch signaling is required for the differentiation of Tfh cells and is known to influence cytokine production in T cells, we hypothesized that Notch signaling also plays an important role in regulating the function and maintenance of Tfh cells. Intestinal helminth infection was used to characterize whether persistent Notch signaling is required to maintain Tfh cell fate and function during allergic immunity. The use of intestinal helminths also allows us to assess the role of Notch signaling in lung Th2 cells. Deletion of Notch receptors on T cells of infected mice results in reduced IL-4 production by Tfh and Th2 cells. Despite similar reductions in IL-4 production, Th2 immunity remains intact while Tfh functionality is lost. Overexpression of Notch signaling in CD4+ T cells leads to increased IL-4 production by Tfh cells, but not Th2 cells. While it has been shown that Notch signaling is critical for Tfh differentiation, it is not known if Notch signaling plays a continued role after Tfh differentiation. Inhibition of Notch signaling after Tfh differentiation results in decreased expression of CXCR5 and aberrant localization of IL-4 producing T-cells in the lymph node. These findings suggest that Notch signaling is not only important for Tfh differentiation, but that it is also important for regulating Tfh cell fate, function, and maintenance.