Shimpei Kawamoto

Foxp3+ follicular regulatory T cells control the germinal center response

Follicular helper (TFH) cells provide crucial signals to germinal center B cells undergoing somatic hypermutation and selection that results in affinity maturation. Tight control of TFH numbers maintains self tolerance. We describe a population of Foxp3+Blimp-1+CD4+ T cells constituting 10–25% of the CXCR5highPD-1highCD4+ T cells found in the germinal center after immunization with protein antigens. These follicular regulatory T (TFR) cells share phenotypic characteristics with TFH and conventional Foxp3+ regulatory T (Treg) cells yet are distinct from both. Similar to TFH cells, TFR cell development depends on Bcl-6, SLAM-associated protein (SAP), CD28 and B cells; however, TFR cells originate from thymic-derived Foxp3+ precursors, not naive or TFH cells. TFR cells are suppressive in vitro and limit TFH cell and germinal center B cell numbers in vivo. In the absence of TFR cells, an outgrowth of non–antigen-specific B cells in germinal centers leads to fewer antigen-specific cells. Thus, the TFH differentiation pathway is co-opted by Treg cells to control the germinal center response.

Preferential Generation of Follicular B Helper T Cells from Foxp3+ T Cells in Gut Peyer's Patches

Most of the immunoglobulin A (IgA) in the gut is generated by B cells in the germinal centers of Peyers patches through a process that requires the presence of CD4+ follicular B helper T(TFH) cells. The nature of these TFH cells in Peyers patches has been elusive. Here, we demonstrate that suppressive Foxp3+CD4+ T cells can differentiate into TFH cells in mouse Peyers patches. The conversion of Foxp3+ T cells into TFH cells requires the loss of Foxp3 expression and subsequent interaction with B cells. Thus, environmental cues present in gut Peyers patches promote the selective differentiation of distinct helper T cell subsets, such as TFH cells.

Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis.

In mammals, the gastrointestinal tract harbors an extraordinarily dense and complex community of microorganisms. The gut microbiota provide strong selective pressure to the host to evolve adaptive immune responses required for the maintenance of local and systemic homeostasis. The continuous antigenic presence in the gut imposes a dynamic remodeling of gut-associated lymphoid tissues (GALT) and the selection of multiple layered strategies for immunoglobulin (Ig) A production. The composite and dynamic gut environment also necessitates heterogeneous, versatile, and convertible T cells, capable of inhibiting (Foxp3(+) T cells) or helping (T(FH) cells) local immune responses. In this review, we describe recent advances in our understanding of dynamic pathways that lead to IgA synthesis, in gut follicular structures and in extrafollicular sites, by T cell-dependent and T cell-independent mechanisms. We discuss the finely tuned regulatory mechanisms for IgA production and emphasize the role of mucosal IgA in the selection and maintenance of the appropriate microbial composition that is necessary for immune homeostasis.

The Inhibitory Receptor PD-1 Regulates IgA Selection and Bacterial Composition in the Gut

Gut Reaction The gut needs to keep its trillions of microbial inhabitants contained. The immune system has evolved a multifaceted approach to this problem, which includes the production of large quantities of immunoglobulin A (IgA) in the intestinal mucosa. In a process that is not well understood, plasma cells that produce IgA specific for the gut microflora are selected in Peyers patches in the gut. Kawamoto et al. (p. 485) used genetically manipulated mice to show that the inhibitory co-receptor, programmed cell death-1 (PD-1), is required for the proper selection IgA-secreting cells in the gut. The effect of PD-1 deletion, however, was not intrinsic to the B cells that produce IgA. Instead, the absence of PD-1 affected the differentiation of T follicular helper cells, which provide important signals to B cells that help guide them as they develop the capacity to produce microflora-specific IgA. Mice deficient in PD-1 exhibited alterations in the composition in their microflora, which suggests that defective selection of IgA can perturb the careful balance that exists between the immune system and resident bacteria. An inhibitory receptor is important for gut microflora containment by immunoglobulin A. Immunoglobulin A (IgA) is essential to maintain the symbiotic balance between gut bacterial communities and the host immune system. Here we provide evidence that the inhibitory co-receptor programmed cell death–1 (PD-1) regulates the gut microbiota through appropriate selection of IgA plasma cell repertoires. PD-1 deficiency generates an excess number of T follicular helper (TFH) cells with altered phenotypes, which results in dysregulated selection of IgA precursor cells in the germinal center of Peyer’s patches. Consequently, the IgAs produced in PD-1–deficient mice have reduced bacteria-binding capacity, which causes alterations of microbial communities in the gut. Thus, PD-1 plays a critical role in regulation of antibody diversification required for the maintenance of intact mucosal barrier.

The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells

Foxp3+ regulatory T (Treg) cells in visceral adipose tissue (VAT-Treg cells) are functionally specialized tissue-resident cells that prevent obesity-associated inflammation and preserve insulin sensitivity and glucose tolerance. Their development depends on the transcription factor PPAR-γ; however, the environmental cues required for their differentiation are unknown. Here we show that interleukin 33 (IL-33) signaling through the IL-33 receptor ST2 and myeloid differentiation factor MyD88 is essential for development and maintenance of VAT-Treg cells and sustains their transcriptional signature. Furthermore, the transcriptional regulators BATF and IRF4 were necessary for VAT-Treg differentiation through direct regulation of ST2 and PPAR-γ expression. IL-33 administration induced vigorous population expansion of VAT-Treg cells, which tightly correlated with improvements in metabolic parameters in obese mice. Human omental adipose tissue Treg cells also showed high ST2 expression, suggesting an evolutionarily conserved requirement for IL-33 in VAT-Treg cell homeostasis.

The Sensing of Environmental Stimuli by Follicular Dendritic Cells Promotes Immunoglobulin A Generation in the Gut

In the Peyers patches (PPs), germinal centers (GCs) are chronically induced by bacteria and are the major sites for generation of gut immunoglobulin A (IgA) immune responses. Whether follicular dendritic cells (FDCs) within the GCs directly contribute to the IgA production in PPs is unknown. We showed here that direct stimulation of FDCs by bacterial products and retinoic acid synergistically enhanced the expression of the chemokine CXCL13, the survival factor BAFF, and molecules that facilitate the secretion and activation of the cytokine TGF-beta1. A reduced production of these molecules by PP FDCs associated with deficiencies in the Toll-like receptor pathway or vitamin A resulted in decreased numbers of GC B cells and defective generation of IgA(+) B cells within PP GCs. Our data indicate that PP FDCs are conditioned by environmental stimuli to express key factors for B cell migration, survival, and preferential generation of IgA in gut.

GALT: Organization and Dynamics Leading to IgA Synthesis

Since its discovery more than four decades ago, immunoglobulin (Ig) A has been the subject of continuous and intensive studies. The major concepts derived were that the precursors of IgA plasma cells are generated in follicular organized structures with the help of T cells and the secreted IgAs provide protection against mucosal pathogens. However, only recently we began to appreciate that IgAs play key roles in regulation of bacterial communities in the intestine and that the repertoire of gut microbiota is closely linked to the proper functioning of the immune system. In this review, we highlight the complex and dynamic mutualistic relationships between bacteria and immune cells and discuss the sites and pathways leading to IgA synthesis in gut-associated lymphoid tissues (GALT).

Roles of B-1 and B-2 cells in innate and acquired IgA-mediated immunity

Summary:  The gut harbors an extremely dense and complex community of microorganisms that are in constant dialog with our immune cells. The gut bacteria provide strong selective pressure to the host to evolve innate and adaptive immune responses required for the maintenance of local and systemic homeostasis. One of the most conspicuous responses of the gut immune system following microbial colonization is the production of immunoglobulin A (IgA). In this review, we discuss the roles of B‐1 and B‐2 cells in IgA‐mediated immunity and present an updated view for the sites and mechanisms of IgA synthesis in the gut. We summarize the role of secretory IgAs for regulation of microbial communities and provide clues as to how the gut microbiota contributes to the development of the gut‐associated lymphoid tissues.

Gut TFH and IgA: key players for regulation of bacterial communities and immune homeostasis

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+ T cells in germinal centers (GCs). We discuss the finely tuned regulatory mechanisms for IgA synthesis in GCs of Peyers patches and emphasize the roles of CD4+ T cells for IgA selection and the maintenance of appropriate gut microbial communities required for immune homeostasis.

Critical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel disease

Bcl11b is required for optimal FoxP3 expression and suppressor function by regulatory T cells and for the generation of inducible regulatory T cells.