BACKGROUND: Th2 cells have long been considered responsible for the switching of B cells to production of IgE during cognate interaction, primarily due to their expression of CD40L and secretion of IL-4. This concept has been challenged by the more recent definition of follicular helper T cells (Tfh) as the key T cell subset in B cell isotype switching, due to their physical location at the boundary of T cell:B cell areas in lymphoid follicles and ability to express IL-4 and CD40L. OBJECTIVE: To determine whether Tfh cells are responsible for IgE responses to Der p 1 allergen after house dust mite (HDM)-induced allergic sensitization. METHODS: Mice deficient in Tfh cells were sensitized to HDM and Der p 1-specific IgE measured by ELISA. RESULTS: Mice with a mutation in T cell-expressed IL-6R were unable to expand Tfh populations after HDM sensitization, and their anti-Der p 1 IgE, IgG1 and total IgE responses were reduced by 80-90% compared with wild-type mice. These animals displayed unaltered lung Th2 and eosinophilic responses after intranasal HDM challenge and normal IL-4 production, but B cell infiltration of the airways was abrogated. CONCLUSIONS AND CLINICAL RELEVANCE: Our data indicate that Tfh cells are largely responsible for switching B cells to IgE synthesis, most likely via an IgG1(+) intermediate. However, Th2 cells are the major source of IL-4 during HDM sensitization and this might contribute to IgE synthesis at a stage distal to Tfh-mediated isotype switching. The IL-6/follicular helper T cell pathway is a potential therapeutic target in allergic disease.