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Coordination between inductive and effector sites for the induction and regulation of antigen-specific mucosal immune responses. Antigens in the lumens of the gastrointestinal tract, nasal cavity, and tear ducts are endocytosed by M cells located on the follicle-associated epithelium (FAE) of the mucosa-associated lymphoid tissues. In the case of gut-associated lymphoid tissue or Peyer’s patches, M cells located in the FAE form the subepithelial dome structure, and antigen-presenting cells such as dendritic cells (DCs) lie immediately beneath the FAE. M-cell–endocytosed antigens are immediately processed by DCs, which transport antigens to underlying T cell zones through molecular interactions such as CCL19–CCR7 and CCL20–CCR6. Antigen-primed T cells support the induction of IgA-committed B cells (IgA⁺ B cells) owing to the biologic influences of transforming growth factor (TGF)-β, IL-2, IL-5, IL-6, IL-10, and the CD40–CD40 ligand (CD40L) interaction. In addition, IgA⁺ B cells acquire mucosal-imprinting molecules, such as CCR9, CCR10, and α4β7 integrin, and subsequently migrate to the effector sites. At the effector sites (e.g., the intestinal lamina propria), IgA⁺ B cells differentiate into plasma cells after stimulation by the IgA-enhancing cytokines IL-5, IL-6, and IL-10, which are secreted by antigen-specific Th2 cells. Dimeric or polymeric IgA secreted from plasma cells is transported to the mucosal surface as secretory IgA (SIgA) through the binding to polymeric Ig receptor expressed on the basal membrane of epithelial cells (ECs).

The mucosal immune system consists of coordinated inductive and effector tissues (Fig. ​(Fig.11).²⁾ As inductive sites, MALTs are equipped with all of the immunocompetent cells needed to initiate antigen-specific humoral and cell-mediated immune responses.^22–24) For example, at Peyer’s patches (PPs), which are well characterized GALT components, orally administered antigens are taken up by M cells located in the follicle-associated epithelium; M cells promptly deliver antigens to antigen-presenting cells, such as dendritic cells and macrophages, that lie beneath PPs.²⁴⁾ Antigen-presenting cells subsequently present processed antigen to naïve T cells, leading to the differentiation to Th1 cells, Th2 cells, Th17 cells, and cytotoxic T cells; they also induce IgA-committed B cells (IgA⁺ B cells) with key immunological molecules (e.g., TGF-β [transforming growth factor β], interleukin (IL)-5, IL-6, IL-10, APRIL [a proliferation-inducing ligand] and BAFF [B cell activating factor]), leading to the initiation of antigen-specific immune responses.²⁴⁾ Concurrent with antigen presentation, dendritic cells located in PPs induce gut-imprinting molecules (e.g., CC chemokine receptor [CCR]9, CCR10, α4β7 integrin) on antigen-specific lymphocytes through the retinoic acid cascade for their subsequent migration to the effector tissues (e.g., intestinal lamina propria) (Fig. ​(Fig.11).^25,26) The lipid mediator system, which includes sphingosine-1-phosphate and its receptor, sphingosine-1-phosphate receptor type 1, plays an essential role in the egress from PPs of antigen-specific lymphocytes that carry gut-imprinting molecules and in their subsequent immunologic journey to distant effector sites.^27–29)

At the effector sites, PP-originated antigen-specific Th2 cells provide the IgA-enhancing cytokines (including IL-5, IL-6, and IL-10) needed for the final differentiation of IgA⁺ B cells into plasma cells that produce dimeric or polymeric forms of IgA.^2,24,30,31) These IgA antibodies then bind to poly-Ig receptors expressed on the basal membrane of epithelial cells, where they form SIgA and are transported to gut secretions (Fig. ​(Fig.11).^32,33) This collaborative and well-orchestrated sequence between the inductive (e.g., PPs) and effector (e.g., intestinal lamina propria) sites provides the immunologic basis for the induction and regulation of antigen-specific immune responses (e.g., SIgA production) at the mucosal surface.