Food antigens suppress small intestinal tumorigenesis.

Food components suppressing small intestinal tumorigenesis are not well-defined partly because of the rarity of this tumor type compared to colorectal tumors. Using mice, a mouse model for intestinal tumorigenesis, and antigen-free diet, we report here that food antigens serve this function in the small intestine. By depleting Peyer's patches (PPs), immune inductive sites in the small intestine, we found that PPs have a role in the suppression of small intestinal tumors and are important for the induction of small intestinal T cells by food antigens.

Regulation of T cell repertoires by commensal microbiota.

The gut microbiota plays an important role in regulating the host immune systems. It is well established that various commensal microbial species can induce the differentiation of CD4 T helper subsets such as Foxp3 regulatory T (Treg) cells and Th17 cells in antigen-dependent manner. The ability of certain microbial species to induce either Treg cells or Th17 cells is often linked to the altered susceptibility to certain immune disorders that are provoked by aberrant T cell response against self-antigens.

Redefining the Foreign Antigen and Self-Driven Memory CD4 T-Cell Compartments Transcriptomic, Phenotypic, and Functional Analyses.

Under steady-state conditions, conventional CD4 T lymphocytes are classically divided into naïve (CD44 CD62L) and memory (CD44 CD62L) cell compartments. While the latter population is presumed to comprise a mixture of distinct subpopulations of explicit foreign antigen (Ag)-specific "authentic" memory and foreign Ag-independent memory-phenotype (MP) cells, phenotypic markers differentially expressed in these two cell types have yet to be identified. Moreover, while MP cells themselves have been previously described as heterogeneous, it is unknown whether they consist of distinct subsets defined by marker expression.

Dietary antigens suppress the proliferation of type 2 innate lymphoid cells by restraining homeostatic IL-25 production.

Dietary antigens affect the adaptive immunity of the host by inducing regulatory T cells and IgE-producing B cells. However, their roles in innate immune compartments such as innate lymphoid cells (ILCs) and intestinal epithelial cells (IECs) are unclear. Here, using antigen-free (AF) mice, which are germ-free (GF) mice fed with amino-acid-based diet, we found dietary proteins suppress the development of GATA-3-expressing ILC2s independent of the adaptive immune cells.

A blend of broadly-reactive and pathogen-selected Vγ4 Vδ1 T cell receptors confer broad bacterial reactivity of resident memory γδ T cells.

Although murine γδ T cells are largely considered innate immune cells, they have recently been reported to form long-lived memory populations. Much remains unknown about the biology and specificity of memory γδ T cells. Here, we interrogated intestinal memory Vγ4 Vδ1 T cells generated after foodborne Listeria monocytogenes (Lm) infection to uncover an unanticipated complexity in the specificity of these cells.

Structural specificities of cell surface β-glucan polysaccharides determine commensal yeast mediated immuno-modulatory activities.

Yeast is an integral part of mammalian microbiome, and like commensal bacteria, has the potential of being harnessed to influence immunity in clinical settings. However, functional specificities of yeast-derived immunoregulatory molecules remain elusive. Here we find that while under steady state, β-1,3-glucan-containing polysaccharides potentiate pro-inflammatory properties, a relatively less abundant class of cell surface polysaccharides, dubbed mannan/β-1,6-glucan-containing polysaccharides (MGCP), is capable of exerting potent anti-inflammatory effects to the immune system.

Establishes Commensalism in Germ-Free Mice Through the Reversible Downregulation of Virulence Gene Expression.

The intestine harbors a complex community of bacterial species collectively known as commensal microbiota. Specific species of resident bacteria, as known as pathobiont, have pathogenic potential and can induce apparent damage to the host and intestinal inflammation in a certain condition. However, the host immune factors that permit its commensalism under steady state conditions are not clearly understood.

Complement C5a promotes antigen cross-presentation by Peyer's patch monocyte-derived dendritic cells and drives a protective CD8 T cell response.

The complement fragment C5a is closely associated with adaptive immune induction in the mucosa. However, the mechanisms that control CD8 T cell responses by C5a have not been extensively explored. This study reveals that C5/C5a in the Peyer's patch (PP) subepithelial dome increases upon oral Listeria infection.

Mucin degrader accelerates intestinal stem cell-mediated epithelial development.

Mucin-degrading bacteria are densely populated in the intestinal epithelium; however, their interaction with intestinal stem cells (ISCs) and their progeny have not been elucidated. To determine whether mucin-degrading bacteria play a role in gut homeostasis, mice were treated with , a specialized species that degrades mucin. Administration of for 4 weeks accelerated the proliferation of Lgr5 ISCs and promoted the differentiation of Paneth cells and goblet cells in the small intestine (SI).

Author Correction: Requirements for the differentiation of innate T-bet memory-phenotype CD4 T lymphocytes under steady state.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Dietary Glucose Consumption Promotes RALDH Activity in Small Intestinal CD103CD11b Dendritic Cells.

Retinal dehydrogenase (RALDH) enzymatic activities catalyze the conversion of vitamin A to its metabolite Retinoic acid (RA) in intestinal dendritic cells (DCs) and promote immunological tolerance. However, precise understanding of the exogenous factors that act as initial trigger of RALDH activity in these cells is still evolving. By using germ-free (GF) mice raised on an antigen free (AF) elemental diet, we find that certain components in diet are critically required to establish optimal RALDH expression and activity, most prominently in small intestinal CD103CD11b DCs (siLP-DCs) right from the beginning of their lives.

Requirements for the differentiation of innate T-bet memory-phenotype CD4 T lymphocytes under steady state.

CD4 T lymphocytes consist of naïve, antigen-specific memory, and memory-phenotype (MP) cell compartments at homeostasis. We recently showed that MP cells exert innate-like effector function during host defense, but whether MP CD4 T cells are functionally heterogeneous and, if so, what signals specify the differentiation of MP cell subpopulations under homeostatic conditions is still unclear. Here we characterize MP lymphocytes as consisting of T-bet, T-bet, and T-bet subsets, with innate, Th1-like effector activity exclusively associated with T-bet cells.

Dietary Antigens Induce Germinal Center Responses in Peyer's Patches and Antigen-Specific IgA Production.

The primary induction sites for intestinal IgA are the gut-associated lymphoid tissues (GALT), such as Peyer's patches (PPs) and isolated lymphoid follicles (ILFs). The commensal microbiota is known to contribute to IgA production in the gut; however, the role of dietary antigens in IgA production is poorly understood. To understand the effect of dietary antigens on IgA production, post-weaning mice were maintained on an elemental diet without any large immunogenic molecules.

Bone marrow CX3CR1+ mononuclear cells relay a systemic microbiota signal to control hematopoietic progenitors in mice.

The microbiota regulate hematopoiesis in the bone marrow (BM); however, the detailed mechanisms remain largely unknown. In this study, we explored how microbiota-derived molecules (MDMs) were transferred to the BM and sensed by the local immune cells to control hematopoiesis under steady-state conditions. We reveal that MDMs, including bacterial DNA (bDNA), reach the BM via systemic blood circulation and are captured by CX3CR1+ mononuclear cells (MNCs).

Food antigens drive spontaneous IgE elevation in the absence of commensal microbiota.

Immunoglobulin E (IgE), a key mediator in allergic diseases, is spontaneously elevated in mice with disrupted commensal microbiota such as germ-free (GF) and antibiotics-treated mice. However, the underlying mechanisms for aberrant IgE elevation are still unclear. Here, we demonstrate that food antigens drive spontaneous IgE elevation in GF and antibiotics-treated mice by generating T helper 2 (T2)-skewed T follicular helper (T) cells in gut-associated lymphoid tissues (GALTs).

Interleukin-2/antibody complex expanding Foxp3 regulatory T cells exacerbates Th2-mediated allergic airway inflammation.

Foxp3＋ regulatory CD4＋ T (Treg) cells play an essential role in preventing overt immune responses against self and innocuous foreign antigens. Selective expansion of endogenous Treg cells in response to the administration of interleukin (IL)-2/antibody complex, such as the IL-2/JES6-1 complex (IL-2C) in mice, is considered an attractive therapeutic approach to various immune disorders. Here, we investigated the therapeutic potential of IL-2C in allergic airway inflammation models.

Gut microbiota regulates lacteal integrity by inducing VEGF-C in intestinal villus macrophages.

A lacteal is a blunt-ended, long, tube-like lymphatic vessel located in the center of each intestinal villus that provides a unique route for drainage of absorbed lipids from the small intestine. However, key regulators for maintaining lacteal integrity are poorly understood. Here, we explore whether and how the gut microbiota regulates lacteal integrity.

Unregulated antigen-presenting cell activation by T cells breaks self tolerance.

T cells proliferate vigorously following acute depletion of CD4 Foxp3 T regulatory cells [natural Tregs (nTregs)] and also when naive T cells are transferred to syngeneic, nTreg-deficient hosts. Here, using mice raised in an antigen-free (AF) environment, we show that proliferation in these two situations is directed to self ligands rather than food or commensal antigens. In both situations, the absence of nTregs elevates B7 expression on host dendritic cells (DCs) and enables a small subset of naive CD4 T cells with high self affinity to respond overtly to host DCs: bidirectional T/DC interaction ensues, leading to progressive DC activation and reciprocal strong proliferation of T cells accompanied by peripheral Treg (pTreg) formation.

Microbiota-Derived Lactate Accelerates Intestinal Stem-Cell-Mediated Epithelial Development.

Symbionts play an indispensable role in gut homeostasis, but underlying mechanisms remain elusive. To clarify the role of lactic-acid-producing bacteria (LAB) on intestinal stem-cell (ISC)-mediated epithelial development, we fed mice with LAB-type symbionts such as Bifidobacterium and Lactobacillus spp. Here we show that administration of LAB-type symbionts significantly increased expansion of ISCs, Paneth cells, and goblet cells.

Cell surface polysaccharides of induce the generation of Foxp3 regulatory T cells.

Dysregulation of intestinal microflora is linked to inflammatory disorders associated with compromised immunosuppressive functions of Foxp3 T regulatory (T) cells. Although mucosa-associated commensal microbiota has been implicated in T generation, molecular identities of the "effector" components controlling this process remain largely unknown. Here, we have defined as a potent inducer of Foxp3 T cells with diverse T cell receptor specificity to dietary antigens, commensal bacteria, and itself.

Spontaneous Proliferation of CD4 T Cells in RAG-Deficient Hosts Promotes Antigen-Independent but IL-2-Dependent Strong Proliferative Response of Naïve CD8 T Cells.

The fast and intense proliferative responses have been well documented for naïve T cells adoptively transferred into chronic lymphopenic hosts. This response known as spontaneous proliferation (SP), unlike antigen-independent lymphopenia-induced proliferation (LIP), is driven in a manner dependent on antigens derived from commensal microbiota. However, the precise nature of the SP response and its impact on homeostasis and function for T cells rapidly responding under this lymphopenic condition are still unclear.

Posterior Retroperitoneoscopic Resection of Extra-adrenal Paraganglioma Located in the Aorto-caval Space.

Background: The posterior retroperitoneoscopic adrenalec tomy has several advantages compared with the transperitoneal approach such as a shorter and more direct route to the target organ, no breach of the intraperitoneal space, and no required retraction of the adjacent organs. It also is a safe procedure with a short learning curve.15 This report presents a challenging case of an extra-adrenal paraganglioma located in the aorto-caval space and managed using the retroperitoneal approach.