Although the variables involved in the switching of B cells to polymeric IgA (pIgA)-producing plasma cells have been studied, many questions remain. In recent years, gene-deleted or knockout mice have contributed to a better understanding of the role of specific cells, cytokines, and surface molecules involved in IgA isotype switching. Presumably, isotype switching occurs in mucosal inductive sites, while IgA production by plasma cells occurs in mucosal effector sites, separating the IgA switching and IgA secretion by B cells into different immune compartments[8]. Each of these stages requires specific signals, such as costimulatory molecules, cytokines, and T-helper cells, to give rise to antigen-specific S-IgA Abs in mucosal effector sites.

Neither Th1- nor Th2-type cytokines contributed significantly to the switching of B cells to surface IgA positive (sIgA+) B cells. This process required the presence of transforming growth factor bð1 (TGF-betað1) (Figure 2), which can activate the switch of B cells to the IgA isotype[9]. TGF-betað1 induces a small proportion (<2%) of B cells to switch to IgA in activated B-cell cultures[9,10]. However, TGF-betað1, when used in combination with additional signals, increased TGF-betað1-induced switching in 10% to 20% of B cells and approached IgA+ B-cell levels observed in Peyers patches[11]. Thus, multiple activation signals contribute to the switch to IgA, i.e., B-cell activation by cross-linking the B-cell antigen receptor, CD40-CD40L interactions to promote switching, TGF-betað1 by directing the switch to IgA, and Th2-type cytokines by increasing the number of post-switch IgA+ B cells and their differentiation into IgA-secreting plasma cells. In addition, activated T cells and dendritic cells from the Peyers patches were more effective in switching sIgM+sIgA- B cells to IgA-producing cells than were T cells and dendritic cells derived from the spleen[12]. This suggests that mucosal inductive sites contain specialized T cells or dendritic cells beneficial for B cells to differentiate into IgA-producing cells.

(click image to zoom) Figure 2. Differentiation and regulation of T-helper subsets and the immune response in the mucosal compartments. Encounter of pathogen-derived antigen or vaccine antigen will stimulate T-helper cells to secrete cytokines. Depending on the stimulus, a Th1 or Th2 cell response is induced. For example, intracellular pathogens will induce production of IL-12/IL-18 by macrophages, activating IFN-gamma? production by NK cells and inducing differentiation to a Th1-mediated immune response, which supports CMI and production of complement-fixing antibodies, presumably by production of cytokines such as IFN-gamma?, IL-2, and TNF-beta?. A Th2 response can be observed upon infection with parasites or upon vaccine administration; this response is characterized by production of cytokines such as IL-4, IL-5, IL-6, IL-10, IL-13 which support humoral immunity. However, for induction of a S-IgA, TGF-beta?1 is required to enable B cells to switch to IgA. TGF-beta?1 production is associated with inhibition of IL-4 production by Th2 cells inhibiting IgE production.

T-cell helper functions play important roles in generating antigen-specific humoral and cell-mediated immunity in both systemic and mucosal compartments. The importance of CD4+ T cells for generating protective immunity is illustrated by the lack of these cells in AIDS patients. The differentiation of Th0 cells into either Th1 or Th2 is driven by cytokines such as interleukin 12 (IL-12), interferon gammað (IFN-gammað), and IL-4, respectively. For example, intracellular pathogens, such as viruses and intracellular bacteria, induce production of IL-12 or IL-18 by activated macrophages, presumably after ingestion of the partuculate pathogen, inducing IFN-gammað production in natural killer (NK) cells, which in turn drives the differentiation of Th0 cells toward a Th1 phenotype producing IFN-gammað, IL-2, and tumor necrosis factor bð (TNF-betað)ð (Figure 2). Murine Th1-type responses are associated with cell-mediated immunity, such as delayed-type hypersensitivity and IgG2a antibody responses[8]. Th0 cells are differentiated into Th2-type cells when soluble exogenous antigen is administered, triggering CD4+, NK1.1+ T cells to produce IL-4. The Th2 cell produces more IL-4, expanding Th2-cells, which support the associated immune response. Th2 cells secrete cytokines such as IL-4, IL-5, IL-6, IL-9, IL-10, IL-13. The production of IL-4 supports IgG1 subclass and IgE production, but other antibodies such as IgG2b and IgA, are also produced during a Th2-dominated response[8].

It is not known whether Th1 or Th2 cells are beneficial for optimal S-IgA production. Historically, Th2-type cytokines were considered major helpers for antibody responses. For example, S-IgA Ab responses were supported by mucosal adjuvants such as cholera toxin, which induced polarized Th2 cell responses[13]. However, S-IgA Ab responses may also be induced through Th1-dominated responses, as observed with intracellular pathogens such as Salmonella in the gastrointestinal tract[14] or influenza virus in the upper respiratory tract[15]. Thus, either Th1 or Th2 cells or a combination of these cell types can support antigen-specific S-IgA Ab responses. In this respect, Th2-type cytokines play a role in terminal differentiation of B cells, that are already committed to IgA[16-18], while the Th1-type cytokine IFN-gammað has been implicated in the induction of the polymeric Ig receptor (pIgR) needed for transport of S-IgA[19]. Cross-inhibition of Th1 and Th2 cell-directed IgG2a and IgE production was mediated through IFN-gammað and IL-4, respectively (Figure 2)[20,21].