Some Treg cells also infiltrate germinal centers to negatively regulate TFH cells and this check details process would lead to higher affinity B-cell responses [[20, 21]]. Finally, mast cells also directly activate B cells to induce IgA production via CD40L, IL-6, and IL-10 [[121]]. This activation

may contribute to TI IgA responses in the intestinal lamina propria. Basophils, an innate cell type closely related to mast cells, also deliver helper signals to B cells via both direct and indirect mechanisms (Fig. 4). Firstly, under certain circumstances, basophils can migrate to draining lymph nodes where they release IL-4 to induce the formation of TH2 cells, an IL-4-producing T-cell subset critically involved in the induction of protective IgG1 and IgE responses against various Protease Inhibitor Library allergens and pathogens, including helminths [[122-125]]. Secondly, after secondary immunization, basophils recognize antigen through prebound antigen-specific IgE generated during a primary immune response [[126]]. Antigen recognition via IgE causes upregulation of CD40L and release of IL-4 and IL-6, which provide antibody-inducing

signals to B cells not only directly, but also indirectly via enhancement of IL-4, IL-6, IL-10, and IL-13 production by TH2 cells [[112, 126]]. Presumably, the antigen-IgE interaction does not trigger pathological release of preformed highly inflammatory compounds, such as histamine, from basophils owing to the low affinity

of IgE for antigen. It must be also noted that IgE can also bind DCs, which raises the possibility that DCs could account for at least part of the Th2-inducing activity ascribed to basophils [[127]]. Basophils may deliver similar B-cell helper signals by interacting with IgD (Fig. 4), an enigmatic antibody isotype released by IgD class-switched plasmablasts originating in the human upper respiratory mucosa [[52, 128]]. In spite of being heavily hypermutated, these IgD antibodies are largely polyreactive and may afford mucosal protection by binding not only to commensals and pathogens but also to their virulence factors [[52, 83, 129, 130]]. In addition to crossing the epithelial barrier to reach the surface of upper respiratory mucosal surfaces, IgD binds to circulating basophils, monocytes, and neutrophils, as well buy Ibrutinib as mucosal mast cells, via an unknown receptor [[52]]. Crosslinking of prebound IgD induces basophil release of BAFF, IL-4, and IL-13, which in turn stimulate B cells to undergo IgM production, as well as CSR to IgG and IgA, in a TI manner [[52]]. CD40L and APRIL further help the activation of B cells by IgD-activated basophils [[52]]. Thus, basophils may utilize both prebound IgE and IgD as immune amplifiers of both systemic and mucosal B-cell responses. TFH cells, TFR cells, NKTFH cells, and Treg cells play a pivotal role in TD antibody responses against microbial proteins.