The main function of the immune system is to protect the host against pathogens. However, unlike the systemic immune system, the gut immune system does not eliminate, but instead nourishes complex bacterial communities and establishes advanced symbiotic relationships. Immunoglobulin A (IgA) is the most abundant antibody isotype in mammals, produced mainly in the gut. The primary function of IgA is to maintain homeostasis at mucosal surfaces, and studies in mice have demonstrated that IgA diversification has an essential role in the regulation of gut microbiota. Dynamic diversification and constant adaptation of IgA responses to local microbiota require expression of activation-induced cytidine deaminase by B cells and control from T follicular helper and Foxp3 þ T cells in germinal centers (GCs). We discuss the finely tuned regulatory mechanisms for IgA synthesis in GCs of Peyer's patches and emphasize the roles of CD4 þ T cells for IgA selection and the maintenance of appropriate gut microbial communities required for immune homeostasis. The intestine is colonized by a large number of microorganisms that are establishing mutualistic relationships with the host. These microorganisms-mainly composed of bacteria and commonly referred as the gut microbiota-not only serve as a natural competitor for pathogens, but also are essential for nutrient processing, development and regulation of the host immune system. 1 Gut microbiota, which are separated from the host by a single layer of epithelial cells, appear to stimulate constitutively the host mucosal immune system. To control the threshold of such stimulation, mammals evolved very sophisticated regulatory immune mechanism in the gut. [2][3][4][5] The gut immune system has some peculiarities when compared with the systemic immune system. These become obvious when considering that it is important not to eliminate but to peacefully coexist with gut microbiota to prevent the expansion of harmful bacteria yet to retain helpful and diversified bacteria. Gut immune system uniquely and constitutively produces large amounts of immunoglobulin A (IgA) in response to the interaction with gut microbiota. Most of these immune responses are generated in gutassociated lymphoid tissues. In this review, we dissect the uniqueness of gut immune responses, focusing on the characteristics of T follicular helper (T FH ) cells in gut and their association with IgA selection and control of gut microbiota.
GUT-ASSOCIATED LYMPHOID TISSUESGut-associated lymphoid tissues are usually divided into two functional compartments: inductive and effector sites. 6,7 The primary inductive sites include organized follicular structures that are present along the wall of intestine, such as Peyer's patches (PPs) and isolated lymphoid follicles. These follicular structures are enriched in B cells interacting with T cells. The lamina propria (LP), particularly of the small intestine (SI), is the main mucosal effector site where many of IgA-producing cells generated in the PPs relocate and reside. The IgAs are ...