Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41590-020-0756-8

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.celrep.2019.10.091

Language：English   Publishing type：Research paper (scientific journal)  

The gut-associated lymphoid tissues (GALTs), including Peyer's patches (PPs), cryptopatches (CPs) and isolated lymphoid follicles (ILFs), establish a host-microbe symbiosis by the promotion of immune reactions against gut microbes. Microfold cell inducer (MCi) cells in GALTs are the recently identified mesenchymal cells that express the cytokine RANKL and initiate bacteria-specific immunoglobulin A (IgA) production via induction of microfold (M) cell differentiation. In the previous study, the Twist2-Cre driver was utilized for gene deletion in mesenchymal cells including MCi cells. In order to investigate MCi cells more extensively, it will be necessary to develop experimental tools in addition to the Twist2-Cre driver mice and characterize such drivers in specificity and efficiency. Here we show that M cell differentiation and IgA production are impaired in the targeted deletion of RANKL by the Col6a1-Cre driver. We compared Col6a1-Cre with Twist2-Cre in terms of the specificity for mesenchymal cells in GALTs. Col6a1-Cre CAG-CAT-EGFP mice exhibited EGFP expression in podoplanin⁺CD31^– cells including MCi cells, while Twist2-Cre mice were shown to target endothelial cells and podoplanin⁺CD31^– cells. Tnfsf11^fl/Δ Col6a1-Cre mice exhibited the absence of M cells and severe IgA reduction together with an alteration in gut microbial composition. Moreover, we analyzed germ free mice to test whether changes in the microbiota are the cause of M cell deficiency. M cell differentiation was normal in the CPs/ILFs of germ free mice, indicating that MCi cells induce M cells independently of microbial colonization. This study demonstrates that Col6a1-Cre driver mice are as useful as Twist2-Cre driver mice for functional analyses of GALT-resident mesenchymal cells, including MCi cells.

DOI： 10.1016/j.bbrc.2017.09.004

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The immune and skeletal systems share a variety of molecules, including cytokines, chemokines, hormones, receptors, and transcription factors. Bone cells interact with immune cells under physiological and pathological conditions. Osteoimmunology was created as a new interdisciplinary field in large part to highlight the shared molecules and reciprocal interactions between the two systems in both heath and disease. Receptor activator of NF-κB ligand (RANKL) plays an essential role not only in the development of immune organs and bones, but also in autoimmune diseases affecting bone, thus effectively comprising the molecule that links the two systems. Here we review the function, gene regulation, and signal transduction of osteoimmune molecules, including RANKL, in the context of osteoclastogenesis as well as multiple other regulatory functions. Osteoimmunology has become indispensable for understanding the pathogenesis of a number of diseases such as rheumatoid arthritis (RA). We review the various osteoimmune pathologies, including the bone destruction in RA, in which pathogenic helper T cell subsets [such as IL-17-expressing helper T (Th17) cells] induce bone erosion through aberrant RANKL expression.Wealso focus on cellular interactions and the identification of the communication factors in the bone marrow, discussing the contribution of bone cells to the maintenance and regulation of hematopoietic stem and progenitors cells. Thus the time has come for a basic reappraisal of the framework for understanding both the immune and bone systems. The concept of a unified osteoimmune system will be absolutely indispensable for basic and translational approaches to diseases related to bone and/or the immune system.

DOI： 10.1152/physrev.00036.2016

Language：English   Publishing type：Research paper (scientific journal)  

Lymph nodes (LNs) are strategically situated throughout the body at junctures of the blood vascular and lymphatic systems to direct immune responses against antigens draining from peripheral tissues. The current paradigm describes LN development as a programmed process that is governed through the interaction between mesenchymal lymphoid tissue organizer (LTo) cells and hematopoietic lymphoid tissue inducer (LTi) cells. Using cell-type-specific ablation of key molecules involved in lymphoid organogenesis, we found that initiation of LN development is dependent on LTi-cell-mediated activation of lymphatic endothelial cells (LECs) and that engagement of mesenchymal stromal cells is a succeeding event. LEC activation was mediated mainly by signaling through receptor activator of NF-κB (RANK) and the non-canonical NF-κB pathway and was steered by sphingosine-1-phosphate-receptor-dependent retention of LTi cells in the LN anlage. Finally, the finding that pharmacologically enforced interaction between LTi cells and LECs promotes ectopic LN formation underscores the central LTo function of LECs.

DOI： 10.1016/j.immuni.2017.05.008

Language：English   Publishing type：Research paper (scientific journal)  

Immunoglobulin A (IgA) maintains a symbiotic equilibrium with intestinal microbes. IgA induction in the gut-associated lymphoid tissues (GALTs) is dependent on microbial sampling and cellular interaction in the subepithelial dome (SED). However it is unclear how IgA induction is predominantly initiated in the SED. Here we show that previously unrecognized mesenchymal cells in the SED of GALTs regulate bacteria-specific IgA production and diversify the gut microbiota. Mesenchymal cells expressing the cytokine RANKL directly interact with the gut epithelium to control CCL20 expression and microfold (M) cell differentiation. The deletion of mesenchymal RANKL impairs M cell-dependent antigen sampling and B cell-dendritic cell interaction in the SED, which results in a reduction in IgA production and a decrease in microbial diversity. Thus, the subepithelial mesenchymal cells that serve as M cell inducers have a fundamental role in the maintenance of intestinal immune homeostasis.

DOI： 10.1038/ni.3732

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Invariant NKT (iNKT) cells differentiate in the thymus into three distinct lineages defined by their cytokine and transcription factor expression. Signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) is essential for early stages of iNKT cell development, but its role during terminal differentiation of iNKT1, iNKT2, or iNKT17 cells remains unclear. Taking advantage of SAP-deficient mice expressing a Vα14-Jα18 TCRα transgene, we found that SAP is critical not only for IL-4 production but also for the terminal differentiation of IL-4-producing iNKT2 cells. Furthermore, without SAP, the IL-17 producing subset is expanded, while IFN-γ-producing iNKT1 differentiation is only moderately compromised. Lack of SAP reduced the expression of the transcription factors GATA-3 and promyelocytic leukemia zinc finger, but enhanced the levels of retinoic acid receptor-related orphan receptor γt. In the absence of SAP, lineage commitment was actually shifted toward the emergence of iNKT17 over iNKT2 cells. Collectively, our data unveil a new critical regulatory function for SAP in thymic iNKT cell fate decisions.

DOI： 10.1002/eji.201646313

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Objective RANKL is mainly expressed by synovial fibroblasts and T cells within the joints of rheumatoid arthritis patients. The relative importance of RANKL expression by these cell types for the formation of bone erosions is unclear. We therefore aimed to quantify the contribution of RANKL by each cell type to osteoclast differentiation and bone destruction during inflammatory arthritis. Methods RANKL was specifically deleted in T cells (Tnfsf11^flox/Δ Lck-Cre), in collagen VI expressing cells including synovial fibroblasts (Tnfsf11^flox/Δ Col6a1-Cre) and in collagen II expressing cells including articular chondrocytes (Tnfsf^11flox/Δ Col2a1-Cre). Erosive disease was induced using the collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA) models. Osteoclasts and cartilage degradation were assessed by histology and bone erosions were assessed by micro-CT. Results The inflammatory joint score during CAIA was equivalent in all mice regardless of cell-targeted deletion of RANKL. Significant increases in osteoclast numbers and bone erosions were observed in both the Tnfsf^11flox/Δ and the Tnfsf11^flox/Δ Lck-Cre groups during CAIA; however, the Tnfsf^11flox/Δ Col6a1-Cre mice showed significant protection against osteoclast formation and bone erosions. Similar results on osteoclast formation and bone erosions were obtained in CIA mice. The deletion of RANKL on any cell type did not prevent articular cartilage loss in either model of arthritis used. Conclusions The expression of RANKL on synovial fibroblasts rather than T cells is predominantly responsible for the formation of osteoclasts and erosions during inflammatory arthritis. Synovial fibroblasts would be the best direct target in RANKL inhibition therapies.

DOI： 10.1136/annrheumdis-2014-207137

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Autoantibody production and immune complex (IC) formation are frequently observed in autoimmune diseases associated with bone loss. However, it has been poorly understood whether ICs regulate bone metabolism directly. Here we show that the level of osteoclastogenesis is determined by the strength of FcRγ signalling, which is dependent on the relative expression of positive and negative FcγRs (FcγRI/III/IV and IIB, respectively) as well as the availability of their ligands, ICs. Under physiological conditions, unexpectedly, FcγRIII inhibits osteoclastogenesis by depriving other osteoclastogenic Ig-like receptors of FcRγ. Fcgr2b-/-mice lose bone upon the onset of a hypergammaglobulinemia or the administration of IgG1 ICs, which act mainly through FcγRIII. The IgG2 IC activates osteoclastogenesis by binding to FcγRI and FcγRIV, which is induced under inflammatory conditions. These results demonstrate a link between the adaptive immunity and bone, suggesting a regulatory role for ICs in bone resorption in general, and not only in inflammatory diseases.

DOI： 10.1038/ncomms7637

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The central nervous system (CNS) is an immunologically privileged site protected from uncontrolled access of T cells by the blood-brain barrier (BBB), which is breached upon autoimmune inflammation. Here we have shown that receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) on T cells regulates C-C type chemokine ligand 20 (CCL20) production by astrocytes and T cell localization in the CNS. Importantly, mice specifically lacking RANKL in T cells were resistant to experimental autoimmune encephalomyelitis (EAE) due to altered T cell trafficking. Pharmacological inhibition of RANKL prevented the development of EAE without affecting the peripheral immune response, indicating that RANKL is a potential therapeutic target for treating autoimmune diseases in the CNS.

DOI： 10.1016/j.immuni.2015.10.017

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Autoimmune diseases often result from an imbalance between regulatory T (T reg) cells and interleukin-17 (IL-17)-producing T helper (T H 17) cells; the origin of the latter cells remains largely unknown. Foxp3 is indispensable for the suppressive function of T reg cells, but the stability of Foxp3 has been under debate. Here we show that T H 17 cells originating from Foxp3 + T cells have a key role in the pathogenesis of autoimmune arthritis. Under arthritic conditions, CD25 lo Foxp3 + CD4 + T cells lose Foxp3 expression (herein called exFoxp3 cells) and undergo transdifferentiation into T H 17 cells. Fate mapping analysis showed that IL-17-expressing exFoxp3 T (exFoxp3 T H 17) cells accumulated in inflamed joints. The conversion of Foxp3 + CD4 + T cells to T H 17 cells was mediated by synovial fibroblast-derived IL-6. These exFoxp3 T H 17 cells were more potent osteoclastogenic T cells than were naive CD4 + T cell-derived T H 17 cells. Notably, exFoxp3 T H 17 cells were characterized by the expression of Sox4, chemokine (C-C motif) receptor 6 (CCR6), chemokine (C-C motif) ligand 20 (CCL20), IL-23 receptor (IL-23R) and receptor activator of NF-κB ligand (RANKL, also called TNFSF11). Adoptive transfer of autoreactive, antigen-experienced CD25 lo Foxp3 + CD4 + T cells into mice followed by secondary immunization with collagen accelerated the onset and increased the severity of arthritis and was associated with the loss of Foxp3 expression in the majority of transferred T cells. We observed IL-17 + Foxp3 + T cells in the synovium of subjects with active rheumatoid arthritis (RA), which suggests that plastic Foxp3 + T cells contribute to the pathogenesis of RA. These findings establish the pathological importance of Foxp3 instability in the generation of pathogenic T H 17 cells in autoimmunity.

DOI： 10.1038/nm.3432

Language：English   Publishing type：Research paper (scientific journal)  

Innate Lymphoid cells (ILCs) are recently defined lymphocytes composed of several subsets such as Natural Killer (NK), Natural Helper (NH) and RORγt+ cells, which have no antigen receptors but exhibit rapid cytokine production after stimulation. Murine RORγt+ ILCs can be classified either as CCR6+c-kit^highIL-7Rahigh or CCR6-NK_p46+ cells. The former ones play roles on the formation of secondary lymphoid tissues and the later ones contribute to the maintenance of intestinal epithelial integrity by producing IL-22. Human fetal intestine, tonsil and lympho nodes harbor both NKp44 positive and negative RORγt+ ILC subsets. Since human Crohn's disease patients have increased number of RORγt+ ILCs in the in‰amed intestine, roles of RORγt+ ILCs on the pathogenesis of Crohn's disease became of great interest.

DOI： 10.2177/jsci.36.11

Language：English   Publishing type：Research paper (scientific journal)  

AbstracyLymphoid tissue development is initiated during embryogenesis by the migration of lymphoid tissue inducer (LTi) cells from the fetal liver to the periphery, where they induce the formation of lymph nodes and Peyer's patches. In the fetal liver, a subset of common lymphoid progenitors (CLPs) that expresses the integrin α4β7 gives rise to LTi cells, a process strictly dependent on the expression of the transcriptional repressor Id2 and the nuclear hormone receptor retinoic acid-related orphan receptor γ t (RORγt). In this study, we show that Id2 and RORγt are sequentially up-regulated during LTi cell development, matching two waves of differentiation with opposite requirements for Notch signaling. Both the expression of Id2 and Notch are required for the generation of α4β7 ⁺ RORγt ^- fetal progenitors, but Notch subsequently blocks progression to the RORγt ⁺ stage and final maturation of LTi cells. Notch is therefore a necessary switch to engage the LTi developmental pathway, but needs to be turned off later to avoid diversion to the T cell fate.

DOI： 10.1084/jem.20111594

Language：English   Publishing type：Research paper (scientific journal)  

The mammalian intestine provides a unique niche for a large community of bacterial symbionts that complements the host in digestive and anabolic pathways, as well as in protection from pathogens. Only a few bacterial phyla have adapted to this predominantly anaerobic environment, but hundreds of different species create an ecosystem that affects many facets of the host's physiology. Recent data show how particular symbionts are involved in the maturation of the immune system, in the intestine and beyond, and how dysbiosis, or alteration of that community, can deregulate immunity and lead to immunopathology. The extensive and dynamic interactions between the symbionts and the immune system are key to homeostasis and health, and require all the blends of so-called regulatory and pro-inflammatory immune reactions. Unfortunately, pro-inflammatory immunity leading to the generation of Th17 cells has been mainly associated with its role in immunopathology. Here we discuss the view that the immune system in general, and type 17 immunity in particular, develop to maintain the equilibrium of the host with its symbionts.

DOI： 10.1111/j.1462-5822.2011.01577.x

Language：English   Publishing type：Research paper (scientific journal)  

Lymphoid cells that express the nuclear hormone receptor RORβ 3t are involved in containment of the large intestinal microbiota and defense against pathogens through the production of interleukin 17 (IL-17) and IL-22. They include adaptive IL-17-producing helper T cells (T_H 17 cells), as well as innate lymphoid cells (ILCs) such as lymphoid tissueĝ€" inducer (LTi) cells and IL-22-producing NKp46⁺ cells. Here we show that in contrast to T_H 17 cells, both types of RORγ t ⁺ ILCs constitutively produced most of the intestinal IL-22 and that the symbiotic microbiota repressed this function through epithelial expression of IL-25. This function was greater in the absence of adaptive immunity and was fully restored and required after epithelial damage, which demonstrates a central role for RORγ t⁺ ILCs in intestinal homeostasis. Our data identify a finely tuned equilibrium among intestinal symbionts, adaptive immunity and RORγ t⁺ ILCs.

DOI： 10.1038/ni.2002

Language：English   Publishing type：Research paper (scientific journal)  

The natural cytotoxicity receptor NKp46 is an activating receptor expressed by several distinct innate lymphoid cell (ILC) subsets, including NK cells, some γδ T cells and intestinal RORγt⁺IL-22⁺ cells (NCR22 cells, IL-22-producing NKp46⁺ cell). NCR22 cells may play a role in mucosal barrier function through IL-22-mediated production of anti-bacterial peptides from intestinal epithelial cells. Previous studies identified a predominant proportion of NCR22 cells in gut cryptopatches (CP), lymphoid structures that are strategically positioned to collect and integrate signals from luminal microbes; however, whether CP or other lymphoid structures condition NCR22 cell differentiation is not known. Programmed and inducible lymphoid tissue development requires cell-surface-expressed lymphotoxin (LT)α₁β₂ heterotrimers (provided by lymphoid tissue inducer (LTi) cells) to signal lymphotoxin-β receptor (LTR)⁺ stromal cells. Here, we analyzed NCR22 cells in LTβR-deficient Ncr1^GFP/+ mice that lack organized secondary lymphoid tissues. We found that NCR22 cells develop in the absence of LTβR, become functionally competent and localize to the lamina propria under steady-state conditions. Following infection of LTβR^-/- mice with the Gram-negative pathogen Citrobacter rodentium, IL-22 production from NCR22 cells was not affected. These results indicate that organized lymphoid tissue structures are not critical for the generation of an intact and fully functional intestinal NCR22 cell compartment.

DOI： 10.1002/eji.201040851

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Retinoic acid-related orphan receptor (ROR)γt⁺ TCRαβ⁺ cells expressing IL-17, termed Th17 cells, are most abundant in the intestinal lamina propria. Symbiotic microbiota are required for the generation of Th17 cells, but the requirement for microbiota-derived Ag is not documented. In this study, we show that normal numbers of Th17 cells develop in the intestine of mice that express a single TCR in the absence of cognate Ag, whereas the microbiota remains essential for their development. However, such mice, or mice monocolonized with the Th17-inducing segmented filamentous bacteria, fail to induce normal numbers of Foxp3⁺ RORγt⁺ T cells, the regulatory counterpart of IL-17 ⁺RORγt⁺ T cells. These results demonstrate that a complex microbiota and cognate Ag are required to generate a properly regulated set of RORγt⁺ T cells and Th17 cells.

DOI： 10.4049/jimmunol.1001723

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The programmed development of lymph nodes and Peyer's patches during ontogeny requires lymphoid tissue inducer (LTi) cells that express the nuclear hormone receptor RORγt. After birth, LTi cells in the intestine cluster into cryptopatches, the precursors of isolated lymphoid follicles (ILFs), which are induced to form by symbiotic bacteria and maintain intestinal homeostasis. We show that in RORγt-deficient mice, which lack LTi cells, programmed lymphoid tissues, ILFs, and Th17 cells, bacterial containment requires the generation of large numbers of tertiary lymphoid tissues (tLTs) through the activity of B cells. However, upon epithelial damage, these mice develop severe intestinal inflammation characterized by extensive recruitment of neutrophils and IgG⁺ B cells, high expression of activation-induced deaminase in tLTs, and wasting disease. The pathology was prevented by antibiotic treatment or inhibition of lymphoid tissue formation and was significantly decreased by treatment with intravenous immunoglobulin G (IVIG). Our data show that intestinal immunodeficiency, such as an absence in RORγt-mediated proinflammatory immunity, can be compensated by increased lymphoid tissue genesis. However, this comes at a high cost for the host and can lead to a deregulated B cell response and aggravated inflammatory pathology.

DOI： 10.1084/jem.20100052

Language：English   Publishing type：Research paper (scientific journal)  

Lymphoid tissue - inducer (LTi) cells initiate the development of lymphoid tissues through the activation of local stromal cells in a process similar to inflammation. LTi cells express the nuclear hormone receptor RORγt, which also directs the expression of the proinflammatory cytokine interleukin-17 in T cells. We show here that LTi cells are part of a larger family of proinflammatory RORγt⁺ innate lymphoid cells (ILCs) that differentiate from distinct fetal liver RORγt⁺ precursors. The fate of RORγt⁺ ILCs is determined by mouse age, and after birth, favors the generation of cells involved in intestinal homeostasis and defense. Contrary to RORγt⁺ T cells, however, RORγt ⁺ ILCs develop in the absence of microbiota. Our study indicates that RORγt⁺ ILCs evolve to preempt intestinal colonization by microbial symbionts.

DOI： 10.1126/science.1194597

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The natural cytotoxicity receptor NKp46 (encoded by Ncr1) was recently shown to identify a subset of noncytotoxic, Rag-independent gut lymphocytes that express the transcription factor Rorc, produce interleukin (IL)-22, and provide innate immune protection at the intestinal mucosa. Intestinal CD3 ^-NKp46⁺ cells are phenotypically heterogeneous, comprising a minority subset that resembles classical mature splenic natural killer (NK) cells (NK1.1⁺, Ly49⁺) but also a large CD127 ⁺NK1.1^- subset of lymphoid tissue inducer (LTi)-like Rorc⁺ cells that has been proposed to include NK cell precursors. We investigated the developmental relationships between these intestinal CD3 ^-NKp46⁺ subsets. Gut CD3^-NKp46⁺ cells were related to LTi and NK cells in requiring the transcriptional inhibitor Id2 for normal development. Overexpression of IL-15 in intestinal epithelial cells expanded NK1.1⁺ cells within the gut but had no effect on absolute numbers of the CD127⁺NK1.1^-Rorc+ subset of CD3^-NKp46⁺ cells. In contrast, IL-7 deficiency strongly reduced the overall numbers of CD3^-NKp46⁺NK1. 1^- cells that express Rorc and produce IL-22 but failed to restrict homeostasis of classical intestinal NK1.1⁺ cells. Finally, in vivo fate-mapping experiments demonstrated that intestinal NK1.1 ⁺CD127^- cells are not the progeny of Rorc-expressing progenitors, indicating that CD127⁺NK1.1^-Rorc⁺ cells are not canonical NK cell precursors. These studies highlight the independent cytokine regulation of functionally diverse intestinal NKp46 ⁺ cell subsets.

DOI： 10.1084/jem.20092029

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Cryptopatches, small aggregates of lymphoid cells found in the intestinal lamina propria, have been assigned many functions specific to gut immunity. Populated with seemingly immature lymphoid cells and dendritic cells, it has been suggested that cryptopatches maturate intraepithelial lymphocytes, Th17 cells, IL-22-producing NKp46⁺ cells, and lymphoid tissues in response to the gut microbiota. Some of these issues, however, remain hotly debated. Therefore, cryptopatches are coming to the forefront of gut immunology and warrant a comprehensive discussion of their role in the development of the immune system.

DOI： 10.1016/j.it.2009.11.004

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Natural killer (NK) cells are innate lymphocytes with spontaneous antitumor activity, and they produce interferon-γ (IFN-γ) that primes immune responses. Whereas T helper cell subsets differentiate from naive T cells via specific transcription factors, evidence for NK cell diversification is limited. In this report, we characterized intestinal lymphocytes expressing the NK cell natural cytotoxicity receptor NKp46. Gut NKp46⁺ cells were distinguished from classical NK cells by limited IFN-γ production and absence of perforin, whereas several subsets expressed the nuclear hormone receptor retinoic acid receptor-related orphan receptor t (RORγt) and interleukin-22 (IL-22). Intestinal NKp46⁺IL-22⁺ cells were generated via a local process that was conditioned by commensal bacteria and required RORγt. Mice lacking IL-22-producing NKp46⁺ cells showed heightened susceptibility to the pathogen Citrobacter rodentium, consistent with a role for intestinal NKp46⁺ cells in immune protection. RORγt-driven diversification of intestinal NKp46⁺ cells thereby specifies an innate cellular defense mechanism that operates at mucosal surfaces.

DOI： 10.1016/j.immuni.2008.11.001

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The nuclear hormone receptor retinoic acid receptor-related orphan receptor γt (RORγt) is required for the generation of T helper 17 cells expressing the proinflammatory cytokine interleukin (IL)-17. In vivo, however, less than half of RORγt⁺ T cells express IL-17. We report here that RORγt⁺ Tαβ cells include Foxp3⁺ cells that coexist with IL-17-producing RORγt⁺ Tαβ cells in all tissues examined. The Foxp3⁺ RORγt⁺ Tαβ express IL-10 and CCL20, and function as regulatory T cells. Furthermore, the ratio of Foxp3⁺ to IL-17-producing RORγt ⁺ Tαβ cells remains remarkably constant in mice enduring infection and inflammation. This equilibrium is tuned in favor of IL-10 production by Foxp3 and CCL20, and in favor of IL-17 production by IL-6 and IL-23. In the lung and skin, the largest population of RORγt⁺ T cells express the γδ T cell receptor and produce the highest levels of IL-17 independently of IL-6. Thus, potentially antagonistic proinflammatory IL-17-producing and regulatory Foxp3⁺ RORγt⁺ T cells coexist and are tightly controlled, suggesting that a perturbed equilibrium in RORγt⁺ T cells might lead to decreased immunoreactivity or, in contrast, to pathological inflammation.

DOI： 10.1084/jem.20080034

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Patients with Omenn syndrome (OS) have hypomorphic RAG mutations and develop varying manifestations of severe combined immunodeficiency. It is not known which symptoms are caused directly by the RAG mutations and which depend on other polymorphic genes. Our current understanding of OS is limited by the lack of an animal model. In the present study, we identified a C57BL/10 mouse with a spontaneous mutation in, and reduced activity of, RAG1. Mice bred from this animal contained high numbers of memory-phenotype T cells and experienced hepatosplenomegaly and eosinophilia, had oligoclonal T cells, and demonstrated elevated levels of IgE, major symptoms of OS. Depletion of CD4⁺ T cells in the mice caused a reduction in their IgE levels. Hence these "memory mutant" mice are a model for human OS; many symptoms of their disease were direct results of the Rag hypomorphism and some were caused by malfunctions of their CD4⁺ T cells.

DOI： 10.1172/JCI30513

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CD1d-restricted NKT cells are activated by TCR-mediated stimulation via CD1d plus lipid antigens such as alpha-galactosylceramide (α-GalCer). These cells suppressed autoimmunity and graft rejection, but sometimes enhanced resistance to infection and tumor immunity. This double-action phenomenon of NKT cells is partly explained by cytokines produced by NKT cells. Therefore, roles of cytokines from activated NKT cells have been extensively examined; however, their roles on T cell homeostatic proliferation in lymphopenic condition have not been investigated. Here, we showed that α-GalCer enhanced homeostatic proliferation of CD8⁺ but not CD4⁺ T cells and this effect of α-GalCer was required for NKT cells. IL-4 was essential and sufficient for this NKT cell action on CD8⁺ T cell homeostatic proliferation. Importantly, the expression of IL-4Rα and STAT6 in CD8⁺ T cells was essential for the NKT activity, indicating a direct action of IL-4 on CD8⁺ T cells. Consistent with this, the level of IL-4Rα expression on memory phenotype CD8⁺ T cells was higher than that on naive phenotype one and CD4⁺ T cells. Thus, these results showed the 'involvement' of IL-4 that is produced from activated NKT cells for CD8⁺ T cell homeostatic proliferation in vivo.

DOI： 10.1093/intimm/dxl073

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Mice homozygous for the F759 mutation in the gp130 interleukin (IL)-6 receptor subunit have enhanced gp130-mediated signal transducer and activator of transcription (STAT)3 activation and spontaneously developed a lymphocyte-mediated rheumatoid arthritis-like joint disease. Here, we show that the development of the disease is dependent on both major histocompatibility complex (MHC) II-restricted CD4⁺ T cells and IL-6 family cytokines. In spite of the necessity for CD4⁺ T cells, the gp130 mutation was only required in nonhemtopoietic cells for the disease. The gp130 mutation resulted in enhanced production of IL-7. Conditional knockout of STAT3 in nonlymphoid cells showed that the enhancement of IL-7 production was dependent on STAT3 activation by IL-6 family cytokines. Homeostatic proliferation of CD4⁺ T cells was enhanced in gp130 mutant mice and acceleration of homeostatic proliferation enhanced the disease, whereas the inhibition of homeostatic proliferation suppressed the disease. Anti-IL-7 antibody treatment inhibited not only the enhanced homeostatic proliferation, but also the disease in gp130 mutant mice. Thus, our results show that autoimmune disease in gp130 mutant mice is caused by increased homeostatic proliferation of CD4⁺ T cells, which is due to elevated production of IL-7 by nonhematopoietic cells as a result of IL-6 family cytokine-gp130-STAT3 signaling. JEM

DOI： 10.1084/jem.20052187

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We found IL-6-STAT3 pathway suppresses MHC class II (MHCII) expression on dendritic cells (DCs) and attenuates T cell activation. Here, we showed that IL-6-STAT3 signaling reduced intracellular MHCII αβ dimmer, Ii, and H2-DM levels in DCs. IL-6-mediated STAT3 activation decreased cystatin C level, an endogenous inhibitor of cathepsins, and enhanced cathepsin activities. Importantly, cathepsin S inhibitors blocked reduction of MHCII αβ dimer, Ii, and H2-DM in the IL-6-treated DCs. Overexpression of cystatin C suppressed IL-6-STAT3-mediated increase of cathepsin S activity and reduction of MHCII αβ dimer, Ii, and H2-DM levels in DCs. Cathepsin S overexpression in DCs decreased intracellular MHCII αβ dimer, Ii, and H2-DM levels, LPS-mediated surface expression of MHCII and suppressed CD4 ⁺ T cell activation. IL-6-gp130-STAT3 signaling in vivo decreased cystatin C expression and MHCII αβ dimer level in DCs. Thus, IL-6-STAT3-mediated increase of cathepsin S activity reduces the MHCII αβ dimer, Ii, and H2-DM levels in DCs, and suppresses CD4⁺ T cell-mediated immune responses.

DOI： 10.1016/j.immuni.2005.09.010

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Mice having a point mutation of IL-6 signal transducer, gp130, named gp130F759 induced a rheumatoid arthritis-like disease. The disease induction is totally dependent on mature lymphocytes, since no arthritis-like disease induced in a double mutant between gp130F759 and RAG2KO mice. We prepared several other double mutants including gp130F759/IgMKO, gp130F759/CD8KO, gp130F759/CIITAKO and gp130F759/CD4KO and analyzed the development of the arthritis. We found that development of the disease attenuated in gp130F759/CIITAKO and gp130F759/CD4KO, suggesting the MHC class II-restricted CD4+ T cells are important for the disease development. We showed memory/activated phenotype of CD4+ T cells increased in gp130F759 mice. Since activation of CD4+ T cells is mainly controlled by dendritic cells (DC) in vivo, we investigated this feature of DC in gp130F759 mice. We isolated DCs from superficial lymph nodes and observed that IL-6-mediated signaling suppresses maturation of DCs in vivo. However, total number of DCs in vivo significantly increased in gp130F759 mice compared with wild type controls. Thus, we hypothesize that the rheumatoid arthritis-like disease in gp130F759 mice is induced by an interaction between CD4+ T cells and DC under gp130F759 signal regulation.

DOI： 10.1016/j.ics.2005.07.096

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The homeostasis of memory CD8⁺ T cells is regulated by cytokines. IL-15 is shown to promote the proliferation of Memory CD8⁺ T cells, while IL-2 suppresses their division in vivo. This inhibitory efect of IL-2 appears to occur indirectly, through other cell populations including CD25⁺CD4⁺ T cells; however, the details of this mechanism remain unclear. In this study, we show that 1) both Ag-experienced and memory phenotype CD8⁺ T cells divided after the depletion of IL-2 in vivo; 2) this division occurred normally and CD44^highIL-2/ 15Rβ^high CD8⁺ T cells generated after IL-2 depletion in IL-15 knockout (KO) and in IL-7-depleted IL-15 KO mice; 3) surprisingly, the blockade of IL-2/15Rβ signaling in IL-2-depleted IL-15 KO mice completely abolished the division of memory CD8⁺ T cells, although the only cytokines known to act through IL-2/15Rβ are IL-2 and IL-15; and 4) the expression of IL-2/15Rβ molecules on memory CD8⁺ T cells was required for their division induced by IL-2 depletion. These results demonstrate that the depletion of IL-2 in vivo induced memory CD8⁺ T cell division by an IL-15-independent but by an IL-2/15Rβ-dependent mechanism, suggesting the existence of a novel IL-2/15Rβ-utilizing cytokine that acts directly on memory CD8⁺ T cells to promote cell division.

Language：English   Publishing type：Research paper (scientific journal)  

Dendritic cells (DCs) orchestrate immune responses according to their state of maturation. In response to infection, DCs differentiate into mature cells that initiate immune responses, while in the absence of infection, most of them remain in an immature form that induces tolerance to self Ags. Understanding what controls these opposing effects is an important goal for vaccine development and prevention of unwanted immune responses. A crucial question is what cytokine(s) regulates DC maturation in the absence of infection. In this study, we show that IL-6 plays a major role in maintaining immature DCs. IL-6 knockout (KO) mice had increased numbers of mature DCs, indicating that IL-6 blocks DC maturation in vivo. We examined this effect further in knockin mice expressing mutant versions of the IL-6 signal transducer gp130, with defective signaling through either Src homology region 2 domain-containing phosphatase 2/GabMAPK (gp130^F759/F759) or STAT3 (gp130^FxxQ/FxxQ), and combined gp130 and IL-6 defects (gp130^F759/F759/IL-6 KO mice). Importantly, we found STAT3 activation by IL-6 was required for the suppression of LPS-induced DC maturation. In addition, STAT3 phosphorylation in DCs was regulated by IL-6 in vivo, and STAT3 was necessary for the IL-6 suppression of bone marrow-derived DC activation/maturation. DC-mediated T cell activation was enhanced in IL-6 KO mice and suppressed in gp130^F759/F759 mice. IL-6 is thus a potent regulator of DC differentiation in vivo, and IL-6-gp130-STAT3 signaling in DCs may represent a critical target for controlling T cell-mediated immune responses in vivo.

DOI： 10.4049/jimmunol.173.6.3844

Language：English   Publishing type：Research paper (scientific journal)  

Rheumatoid arthritis (RA) is a polygenic autoimmune disease. The autoimmunity develops from synergistic actions of genetic and environmental factors. We generated a double-mutant mouse by crossing two murine models of RA, a gp130 mutant knock-in mouse (gp130^F759/F759) and an HTLV-1 pX transgenic mouse (pX-Tg), in a C57BL/6 background, which is resistant to arthritis. The mice spontaneously developed severe arthritis with a much earlier onset than the gp130^F759/F759 mice and with a much higher incidence than did the pX-Tg mice. The symptoms of gp130^F759/F759 mice, including lymphoadenopathy, splenomegaly, hyper-γ-globulinemia, autoantibody production, increases in memory/activated T cells and granulocytes in the peripheral lymphoid organs, and a decrease in the class II MHC^bright CD11c⁺ population, were augmented in the double mutants. Marked reductions in incidence, severity and immunological abnormalities were seen in the triple mutant, IL-6^-/-/gp130^F759/F759/pX-Tg, indicating that the arthritis in the double mutant is IL-6 dependent. gp130^F759/F759/pX-Tg is a unique mouse model for RA.

DOI： 10.1093/intimm/dxh045

Event date： 2024.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：京都大学芝蘭会館（京都）   Country：Japan  

Event date： 2024.6

Language：Japanese   Presentation type：Poster presentation  

Venue：京都大学芝蘭会館（京都）   Country：Japan  

Event date： 2024.2

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：オンライン   Country：Japan  

Event date： 2024.1

Language：Japanese  

Venue：幕張メッセ（千葉）   Country：Japan  

Event date： 2024.1

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：幕張メッセ（千葉）   Country：Japan  

Event date： 2024.1

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：幕張メッセ（千葉）   Country：Japan  

Event date： 2024.1

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：幕張メッセ（千葉）   Country：Japan  

Event date： 2023.12

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：静岡県立大学   Country：Japan  

Event date： 2023.10

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：オンライン(Zoom)   Country：Japan  

Event date： 2023.9

Language：Japanese  

Venue：東京国際フォーラム（東京）   Country：Japan  

Event date： 2023.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：京都みやこめっせ   Country：Japan  

Event date： 2023.8

Language：Japanese  

Venue：福岡アイランドシティフォーラム（福岡）   Country：Japan  

Event date： 2023.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡アイランドシティフォーラム （福岡）   Country：Japan  

Event date： 2023.8

Language：Japanese  

Venue：福岡アイランドシティフォーラム （福岡）   Country：Japan  

Event date： 2023.7

Language：Japanese  

Venue：熊本城ホール（熊本）   Country：Japan  

Event date： 2023.7

Language：Japanese  

Venue：都市センターホテル （東京）   Country：Japan  

Event date： 2023.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：京都大学芝蘭会館（京都）   Country：Japan  

Event date： 2023.6

Language：Japanese  

Venue：御茶ノ水ソラシティカンファレンスセンター　（東京）   Country：Japan  

Event date： 2023.6

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：徳島大学　大塚記念講堂   Country：Japan  

Event date： 2023.6

Language：Japanese  

Venue：徳島大学　大塚記念講堂   Country：Japan  

Event date： 2023.5 - 2024.5

Language：English  

Venue：和歌山   Country：Japan  

Event date： 2023.4

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：神戸国際会議場（神戸）   Country：Japan  

Event date： 2023.3

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：鹿児島ライカ   Country：Japan  

Event date： 2022.12

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：大阪大学   Country：Japan  

Event date： 2022.12

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2022.12

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：熊本城ホール   Country：Japan  

Event date： 2022.12

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：熊本城ホール   Country：Japan  

Event date： 2022.12

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：熊本城ホール   Country：Japan  

Event date： 2022.12

Language：English   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2022.11

Language：English   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2022.9

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：大阪大学微生物業研究所 谷口記念講堂   Country：Japan  

Event date： 2022.8

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：京都みやこめっせ   Country：Japan  

Event date： 2022.8 - 2023.8

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：大阪大学会館   Country：Japan  

Event date： 2022.7 - 2023.7

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：熊本城ホール/オンライン   Country：Japan  

Event date： 2022.7

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：長良川国際会議場・都ホテル 岐阜長良川   Country：Japan  

Event date： 2022.7

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2022.5

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：オンライン   Country：Japan  

Event date： 2022.5

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：オンライン   Country：Japan  

Event date： 2022.2

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：on line   Country：Japan  

Event date： 2022.1

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：オンライン   Country：Japan  

Event date： 2022.1

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：オンライン   Country：Japan  

Event date： 2021.12

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：奈良   Country：Japan  

Event date： 2020.12

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：アクトシティ浜松   Country：Japan  

Event date： 2020.11

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：ホテルオークラ　福岡   Country：Japan  

Event date： 2020.10

Language：Japanese  

Venue：神戸国際会議場   Country：Japan  

Event date： 2020.9

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：Web   Country：Japan  

Lymph node (LN) is a highly organized immune tissue that initiates acquired immune response against pathogens drained from peripheral tissues. LN development is currently described as a programmed process governed through stepwise activation of three types of cells; lymphatic endothelial cell (LEC), hematopoietic lymphoid tissue inducer (LTi) cell and mesenchymal cell. However, it is still unknown which type of cells initiate complex LN formation process.
Recently, we identified particular mesenchymal cells indispensable for LN formation. In this presentation, we would like to propose novel LN development model; particular mesenchymal cells appear prior to LTi cell colonization, eventually activate neighboring mesenchymal cells and finally build up complex stromal network in the mature LN.

Event date： 2020.9

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：熊本城ホール内シビックホール／Web   Country：Japan  

造血幹細胞から分化発生するリンパ球や骨髄球などの免疫細胞は生体防御を担う中核的な存在である。我々は、免疫細胞が維持され免疫応答の場として機能するリンパ節や造血の場として重要な骨髄が個体発生の過程でどのように構築されるか、という観点から研究を進めてきた。
　胎児期におけるリンパ節形成は自然リンパ球系の細胞であるLymphoid Tissue inducer (LTi) 細胞と間葉系細胞の相互活性化が最初の引き金になると考えられてきた。LTi細胞が発現するLymphotoxin (LT)12はリンパ節形成に必須のサイトカインであるが、その受容体LTbRの発現には特異性がなく、何が「リンパ節を形成する場所」を決めているか不明であった。我々はLTi細胞におけるLT12発現を増強させる特殊な間葉系細胞をリンパ節原基に同定した。この間葉系細胞特異的にLTbR発現を欠損させるとリンパ節の形成は完全に阻害されたことから、この細胞こそがリンパ節形成に必須の間葉系細胞であると結論付けた。
　骨髄がどのようなメカニズムで硬い骨の中に構築され、造血を担うようになるかほとんど明らかになっていない。我々はマクロファージ系の細胞である破骨細胞を欠損するマウスで骨髄腔が形成されないことに注目し、破骨細胞が骨髄空間の形成に果たす役割について検討した。詳細な検討の結果、胎生15日に骨中央部に形成される軟骨膜付近に破骨細胞の誘導に必須の間葉系細胞が出現することを突き止めた。これらの間葉系細胞は自身が骨基質を形成するとともに骨髄ストローマ細胞へ分化する。破骨細胞が存在しない条件下では骨髄内での骨化が進み、造血に有効な骨髄空間が得られず、出生後の造血障害を引き起こすことが明らかになった。
　出生直後における外来微生物との遭遇を予見し、胎児期からリンパ節や骨髄を予め構築しておくことは生体防御の観点から大変理に適ったシステムであると考えられる。

Event date： 2020.6

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：Fransis-Crick Institute   Country：United Kingdom  

Event date： 2020.2

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2020.1

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Country：Japan  

Event date： 2019.10

Language：English   Presentation type：Oral presentation (general)  

Venue：大阪大学　銀杏会館   Country：Japan  

Event date： 2019.8

Language：English   Presentation type：Oral presentation (general)  

Venue：徳島大学　先端酵素学研究所   Country：Japan  

Event date： 2019.6

Language：English   Presentation type：Oral presentation (general)  

Venue：The Francis Crick Institute (London)   Country：United Kingdom  

Other Link： https://www.eventbrite.co.uk/e/jsps-crick-symposium-on-gut-circuits-tickets-58644719936#

Event date： 2019.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：京都大学芝蘭会館   Country：Japan  

Event date： 2019.6

Language：Japanese  

Venue：京都大学芝蘭会館（京都市）   Country：Japan  

【背景・目的】
ストローマ細胞は成熟リンパ節の機能的分画化と構造維持に重要な間葉系細胞であるが、その起源や分化過程は詳細に検討されていない。昨年の本学会において、リンパ節原基中のRANKL陽性細胞がリンパ節初期発生に必須の間葉系細胞（Lymphoid Tissue organizer=LTo細胞）としてLTbRシグナルを伝達することを報告した。今回我々は、RANKL発現細胞とリンパ節ストローマ細胞の細胞系譜関係の解明を目的とした。
【方法・結果】
まず、Brainbawシステムを用い、リンパ節ストローマ細胞が複数のRANKL発現細胞に由来することを明らかにした。次に、Tnfsf11tTA/+ マウスを新規作成し、ドキシサイクリンを用いたRANKL 陽性細胞の時期特異的な標識・追跡系を樹立した。鼠径部リンパ節では、T細胞領域を構成するFRCが胎齢16日目以降のRANKL陽性細胞に由来すること、リンパ節辺縁部に存在するMRCは出生後にRANKLを発現した間葉系細胞に由来することを明らかにした。一方、胎齢15日目でリンパ節原基に生着したRANKL陽性間葉系を標識しても殆どのリンパ節ストローマ細胞は標識されなかった。
【結論・考察】
リンパ節ストローマ細胞の多くは胎仔期に存在するRANKL発現細胞に由来するが、幹細胞のように単一のLTo細胞が自己複製と成熟過程を経て全リンパ節ストローマ細胞へと分化する可能性は極めて低い。リンパ節分画をstep-by-stepに構築し、リンパ球を効率的に集簇させるためには、複数の間葉系細胞においてRANKL発現が連鎖的に誘導されるモデルがより適切と考えられる。

Event date： 2019.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：京都大学芝蘭会館（京都市）   Country：Japan  

Event date： 2019.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：京都大学芝蘭会館（京都市）   Country：Japan  

Event date： 2018.12

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：福岡国際会議場（福岡市）   Country：Japan  

Event date： 2018.12

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：福岡国際会議場（福岡市）   Country：Japan  

Event date： 2018.11 - 2018.12

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：伊藤国際学術交流センター（東京都文京区）   Country：Japan  

Event date： 2018.9

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：札幌市   Country：Japan  

Event date： 2018.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：札幌市   Country：Japan  

Event date： 2018.7

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：東京都新宿区   Country：Japan  

Event date： 2018.7

Language：Japanese  

Venue：東京都品川区   Country：Japan  

Event date： 2018.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：長崎市   Country：Japan  

Event date： 2018.5 - 2018.6

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：東京都台東区   Country：Japan  

Type：Competition, symposium, etc. 

Number of participants：2,000

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：8

Type：Competition, symposium, etc. 

Number of participants：3,000

Type：Competition, symposium, etc. 

Number of participants：300

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：3

Proceedings of International Conference Number of peer-reviewed papers：35

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：3

Proceedings of domestic conference Number of peer-reviewed papers：15

Type：Competition, symposium, etc. 

Number of participants：2,000