研究者詳細 - 高橋　大輔

論文 - 高橋　大輔

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AP-1B regulates interactions of epithelial cells and intraepithelial lymphocytes in the intestine.

Matsumoto R, Ogata K, Takahashi D, Kinashi Y, Yamada T, Morita R, Tanaka K, Hattori K, Endo M, Fujimura Y, Sasaki N, Ohno H, Ishihama Y, Kimura S, Hase K

Cellular and molecular life sciences : CMLS （Springer Science and Business Media LLC） 81 （ 1 ） 425 2024年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1420-682X

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Intestinal epithelium dysfunctions cause IgA deposition in the kidney glomeruli of intestine-specific Ap1m2-deficient mice.

Kinashi Y, Tanaka K, Kimura S, Hirota M, Komiyama S, Shindo T, Hashiguchi A, Takahashi D, Shibata S, Karaki SI, Ohno H, Hase K

EBioMedicine 106 105256 - 105256 2024年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2352-3964

Background: Intestinal epithelial cells (IECs) serve as robust barriers against potentially hostile luminal antigens and commensal microbiota. Epithelial barrier dysfunction enhances intestinal permeability, leading to leaky gut syndrome (LGS) associated with autoimmune and chronic inflammatory disorders. However, a causal relationship between LGS and systemic disorders remains unclear. Ap1m2 encodes clathrin adaptor protein complex 1 subunit mu 2, which facilitates polarized protein trafficking toward the basolateral membrane and contributes to the establishment of epithelial barrier functions. Methods: We generated IEC-specific Ap1m2-deficient (Ap1m2ΔIEC) mice with low intestinal barrier integrity as an LSG model and examined the systemic impact. Findings: Ap1m2ΔIEC mice spontaneously developed IgA nephropathy (IgAN)-like features characterized by the deposition of IgA–IgG immune complexes and complement factors in the kidney glomeruli. Ap1m2 deficiency markedly enhanced aberrantly glycosylated IgA in the serum owing to downregulation and mis-sorting of polymeric immunoglobulin receptors in IECs. Furthermore, Ap1m2 deficiency caused intestinal dysbiosis by attenuating IL-22-STAT3 signaling. Intestinal dysbiosis contributed to the pathogenesis of IgAN because antibiotic treatment reduced aberrantly glycosylated IgA production and renal IgA deposition in Ap1m2ΔIEC mice. Interpretation: IEC barrier dysfunction and subsequent dysbiosis by AP-1B deficiency provoke IgA deposition in the mouse kidney. Our findings provide experimental evidence of a pathological link between LGS and IgAN. Funding: AMED, AMED-CREST, JSPS Grants-in-Aid for Scientific Research, JST CREST, Fuji Foundation for Protein Research, and Keio University Program for the Advancement of Next Generation Research Projects.

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Sugar and arginine facilitate oral tolerance by ensuring the functionality of tolerogenic immune cell subsets in the intestine.

Nagai M, Okawa T, Nakata K, Takahashi D, Miyajima R, Shiratori H, Yamanaka D, Nakamura A, Oyama C, Takahashi SI, Toyama-Sorimachi N, Suzuki K, Ohashi W, Dohi T, Kawamura YI, Hase K

Cell reports （Elsevier BV） 43 （ 7 ） 114490 - 114490 2024年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2211-1247

Although oral tolerance is a critical system in regulating allergic disorders, the mechanisms by which dietary factors regulate the induction and maintenance of oral tolerance remain unclear. To address this, we explored the differentiation and function of various immune cells in the intestinal immune system under fasting and ad libitum-fed conditions before oral ovalbumin (OVA) administration. Fasting mitigated OVA-specific Treg expansion, which is essential for oral tolerance induction. This abnormality mainly resulted from functional defects in the CX3CR1+ cells responsible for the uptake of luminal OVA and reduction of tolerogenic CD103+ dendritic cells. Eventually, fasting impaired the preventive effect of oral OVA administration on asthma and allergic rhinitis development. Specific food ingredients, namely carbohydrates and arginine, were indispensable for oral tolerance induction by activating glycolysis and mTOR signaling. Overall, prior food intake and nutritional signals are critical for maintaining immune homeostasis by inducing tolerance to ingested food antigens.

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A purified diet affects intestinal epithelial proliferation and barrier functions through gut microbial alterations.

Shiratori H, Hattori KM, Nakata K, Okawa T, Komiyama S, Kinashi Y, Kabumoto Y, Kaneko Y, Nagai M, Shindo T, Moritoki N, Kawamura YI, Dohi T, Takahashi D, Kimura S, Hase K

International immunology （Oxford University Press (OUP)） 36 （ 5 ） 223 - 240 2024年01月

研究論文（学術雑誌）, 査読有り, ISSN 0953-8178

The gut microbiota plays a crucial role in maintaining epithelial barrier function. Although multiple studies have demonstrated the significance of dietary factors on gut microbiota and mucosal barrier function, the impact of a purified diet, which has long been used in various animal experiments, on intestinal homeostasis remains to be elucidated. Here, we compared the impact of two different types of diets, a crude diet and an AIN-93G-formula purified diet, on epithelial integrity and the gut microbiota. Purified diet-fed mice exhibited shorter villi and crypt lengths and slower epithelial turnover, particularly in the ileum. In addition, antimicrobial products, including islet-derived protein 3γ (REG3γ), were substantially decreased in purified diet-fed mice. Purified diet feeding also suppressed α1,2-fucosylation on the epithelial surface. Furthermore, purified diet induced metabolic rewiring to fatty acid oxidation and ketogenesis. 16S ribosomal RNA gene sequencing of the ileal contents and mucus layer revealed distinct gut microbiota compositions between the purified and crude diet-fed mice. Purified diet feeding reduced the abundance of segmented filamentous bacteria (SFB), which potently upregulate REG3γ and fucosyltransferase 2 (Fut2) by stimulating group 3 innate lymphoid cells (ILC3) to produce IL-22. These observations illustrate that the intake of a crude diet secures epithelial barrier function by facilitating SFB colonization, whereas a purified diet insufficiently establishes the epithelial barrier, at least partly owing to the loss of SFB. Our data suggest that the influence of purified diets on the epithelial barrier integrity should be considered in experiments using purified diets.

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Safe and efficient oral allergy immunotherapy using one-pot-prepared mannan-coated allergen nanoparticles.

Li S, Toriumi H, Takahashi D, Kamasaki T, Fujioka Y, Nagatoishi S, Li J, Liu Y, Hosokawa T, Tsumoto K, Ohba Y, Katayama Y, Murakami D, Hase K, Mori T

Biomaterials （Elsevier BV） 303 122381 - 122381 2023年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0142-9612

Allergen immunotherapy (AIT) is the only curative treatment for allergic diseases. However, AIT has many disadvantages related to efficiency, safety, long-term duration, and patient compliance. Dendritic cells (DCs) have an important role in antigen-specific tolerance induction; thus, DC-targeting strategies to treat allergies such as glutaraldehyde crosslinked antigen to mannoprotein (MAN) have been established. However, glutaraldehyde crosslinking may reduce the antigen presentation efficiency of DCs. To overcome this, we developed a MAN-coated ovalbumin (OVA) nanoparticle (MDO), which uses intermolecular disulfide bond to crosslink OVA and MAN. MDO effectively targeted DCs resulting in tolerogenic DCs, and promoted higher antigen presentation efficiency by DCs compared with OVA or glutaraldehyde crosslinked nanoparticles. In vitro and in vivo experiments showed that DCs exposed to MDO induced Treg cells. Moreover, MDO had low reactivity with anti-OVA antibodies and did not induce anaphylaxis in allergic mice, demonstrating its high safety profile. In a mouse model of allergic asthma, MDO had significant preventative and therapeutic effects when administered orally or subcutaneously. Therefore, MDO represents a promising new approach for the efficient and safe treatment of allergies.

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α-Glucosidase inhibitors boost gut immunity by inducing IgA responses in Peyer's patches.

Hattori-Muroi K, Naganawa-Asaoka H, Kabumoto Y, Tsukamoto K, Fujisaki Y, Fujimura Y, Komiyama S, Kinashi Y, Kato M, Sato S, Takahashi D, Hase K

Front Immunol. （Frontiers Media SA） 14 1277637 2023年11月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り, ISSN 1664-3224

Peyer’s patches (PPs) are specialized gut-associated lymphoid tissues that initiate follicular helper T (Tfh)-mediated immunoglobulin A (IgA) response to luminal antigens derived from commensal symbionts, pathobionts, and dietary sources. IgA-producing B cells migrate from PPs to the small intestinal lamina propria and secrete IgA across the epithelium, modulating the ecological balance of the commensal microbiota and neutralizing pathogenic microorganisms. α-glucosidase inhibitors (α-GIs) are antidiabetic drugs that inhibit carbohydrate digestion in the small intestinal epithelium, leading to alterations in the commensal microbiota composition and metabolic activity. The commensal microbiota and IgA responses exhibit bidirectional interactions that modulate intestinal homeostasis and immunity. However, the effect of α-GIs on the intestinal IgA response remains unclear. We investigated whether α-GIs affect IgA responses by administering voglibose and acarbose to mice via drinking water. We analyzed Tfh cells, germinal center (GC) B cells, and IgA-producing B cells in PPs by flow cytometry. We also assessed pathogen-specific IgA responses. We discovered that voglibose and acarbose induced Tfh cells, GCB cells, and IgA-producing B cells in the PPs of the proximal small intestine in mice. This effect was attributed to the modification of the microbiota rather than a shortage of monosaccharides. Furthermore, voglibose enhanced secretory IgA (S-IgA) production against attenuated Salmonella Typhimurium. Our findings reveal a novel mechanism by which α-GIs augment antigen-specific IgA responses by stimulating Tfh-GCB responses in PPs, and suggest a potential therapeutic application as an adjuvant for augmenting mucosal vaccines.

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Gut microbiota-derived lipid metabolites facilitate regulatory T cell differentiation.

Shiratori H, Oguchi H, Isobe Y, Han KH, Sen A, Yakebe K, Takahashi D, Fukushima M, Arita M, Hase K

Sci Rep. （Springer Science and Business Media LLC） 13 （ 1 ） 8903 2023年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2045-2322

Commensal bacteria-derived metabolites are critical in regulating the host immune system. Although the impact of gut microbiota-derived hydrophilic metabolites, such as short-chain fatty acids, on immune cell functions and development has been well documented, the immunomodulatory effects of gut microbiota-derived lipids are still of interest. Here, we report that lipid extracts from the feces of specific-pathogen-free (SPF), but not germ-free (GF), mice showed regulatory T (Treg)-cell-inducing activity. We conducted RP-HPLC-based fractionation and liquid chromatography–tandem mass spectrometry (LC–MS/MS)-based lipidome profiling and identified two bioactive lipids, 9,10-dihydroxy-12Z-octadecenoic acid (9,10-DiHOME) and all-trans retinoic acid (atRA), with Treg-inducing activity in vitro. The luminal abundance of 9,10-DiHOME in the large intestine was significantly decreased by dextran sulfate sodium (DSS)-induced colitis, indicating that 9,10-DiHOME may be a potential biomarker of colitis. These observations implied that commensal bacteria-derived lipophilic metabolites might contribute to Treg development in the large intestine.

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Medium-chain fatty acids suppress lipotoxicity-induced hepatic fibrosis via the immunomodulating receptor GPR84

Ryuji Ohue-Kitano, Hazuki Nonaka, Akari Nishida, Yuki Masujima, Daisuke Takahashi, Takako Ikeda, Akiharu Uwamizu, Miyako Tanaka, Motoyuki Kohjima, Miki Igarashi, Hironori Katoh, Tomohiro Tanaka, Asuka Inoue, Takayoshi Suganami, Koji Hase, Yoshihiro Ogawa, Junken Aoki, Ikuo Kimura

JCI insight 8 （ 2 ） e165469 2022年12月

研究論文（学術雑誌）, 共著, 査読有り

Medium-chain triglycerides (MCTs), which consist of medium-chain fatty acids (MCFAs), are unique forms of dietary fat with various health benefits. G protein–coupled 84 (GPR84) acts as a receptor for MCFAs (especially C10:0 and C12:0); however, GPR84 is still considered an orphan receptor, and the nutritional signaling of endogenous and dietary MCFAs via GPR84 remains unclear. Here, we showed that endogenous MCFA-mediated GPR84 signaling protected hepatic functions from diet-induced lipotoxicity. Under high-fat diet (HFD) conditions, GPR84-deficient mice exhibited nonalcoholic steatohepatitis (NASH) and the progression of hepatic fibrosis but not steatosis. With markedly increased hepatic MCFA levels under HFD, GPR84 suppressed lipotoxicity-induced macrophage overactivation. Thus, GPR84 is an immunomodulating receptor that suppresses excessive dietary fat intake–induced toxicity by sensing increases in MCFAs. Additionally, administering MCTs, MCFAs (C10:0 or C12:0, but not C8:0), or GPR84 agonists effectively improved NASH in mouse models. Therefore, exogenous GPR84 stimulation is a potential strategy for treating NASH.

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A Novel HDAC1-Selective Inhibitor Attenuates Autoimmune Arthritis by Inhibiting Inflammatory Cytokine Production.

Zhe W, Hoshina N, Itoh Y, Tojo T, Suzuki T, Hase K, Takahashi D

Biological & pharmaceutical bulletin （Pharmaceutical Society of Japan） 9 （ 1 ） 1364 - 1372 2022年09月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り, ISSN 0918-6158

Rheumatoid arthritis (RA) is systemic autoimmune arthritis that causes joint inflammation and destruction. Accumulating evidence has shown that inhibitors of class I histone deacetylases (HDACs) (i.e., HDAC1, 2, 3, and 8) are potential therapeutic candidates as targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs). Nevertheless, the inhibition of class I HDACs has severe adverse effects because of their broad spectrum. We evaluated the therapeutic effect of a novel selective HDAC1 inhibitor TTA03-107 for collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) models in mice. We also examined the effect of TTA03-107 in bone marrow-derived macrophages (BMDMs) and T helper 17 (Th17) cells in vitro. Here, we delineate that TTA03-107 reduced the severity of autoimmune arthritis without obvious adverse effects in CIA and CAIA models. Moreover, TTA03-107 suppressed the production of inflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-17A, in serum and joint tissue. In vitro treatment of BMDMs with TTA03-107 dampened the M1 differentiation and inflammatory cytokine production. TTA03-107 also suppressed the differentiation of Th17 cells. These results demonstrate that TTA03-107 can attenuate the development of arthritis in experimental RA models by inhibiting the differentiation and activation of macrophages and Th17 cells. Therefore, TTA03-107 is a potential tsDMARD candidate.

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Epithelial HVEM maintains intraepithelial T cell survival and contributes to host protection

Seo, Goo-Young Takahashi, Daisuke Wang, Qingyang Mikulski, Zbigniew Chen, Angeline Chou, Ting-Fang Marcovecchio, Paola McArdle, Sara Sethi, Ashu Shui, Jr-Wen Takahashi, Masumi Surh, Charles D. Cheroutre, Hilde Kronenberg, Mitchell

Science Immunology （AAAS） 7 eabm6931 2022年07月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り

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Retinoid X Receptor Agonist Directed to the Large Intestine Ameliorates T-Cell-Mediated Colitis in Mice

Ryohtaroh Matsumoto, Daisuke Takahashi, Masaki Watanabe, Shunsuke Nakatani, Yuta Takamura, Yuji Kurosaki, Hiroki Kakuta, Koji Hase

Front Pharmacol （Frontiers Media SA） 12 Article 715752 2021年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1663-9812

Retinoid X receptor (RXR) is a nuclear receptor that heterodimerizes with several nuclear receptors, integrating ligand-mediated signals across the heterodimers. Synthetic RXR agonists have been developed to cure certain inflammatory diseases, including inflammatory bowel diseases (IBDs). However, pre-existing RXR agonists, which are lipophilic and readily absorbed in the upper intestine, cause considerable adverse effects such as hepatomegaly, hyperlipidemia, and hypothyroidism. To minimize these adverse effects, we have developed an RXR agonist, NEt-3IB, which has lipophilic and thus poorly absorptive properties. In this study, we evaluated the effects of NEt-3IB in an experimental murine colitis model induced through the adoptive transfer of CD45RBhighCD4+ T cells. Pharmacokinetic studies demonstrated that the major portion of NEt-3IB was successfully delivered to the large intestine after oral administration. Notably, NEt-3IB treatment suppressed the development of T cell-mediated chronic colitis, as indicated by improvement of wasting symptoms, inflammatory infiltration, and mucosal hyperplasia. The protective effect of NEt-3IB was mediated by the suppression of IFN-γ-producing Th1 cell expansion in the colon. In conclusion, NEt-3IB, a large intestine-directed RXR agonist, is a promising drug candidate for IBDs.

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Intestinal immunity: to be, or not to be, induced? That is the question.

Daisuke Takahashi, Shunsuke Kimura, Koji Hase

International immunology （International Immunology） 33 （ 12 ） 755 - 759 2021年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09538178

The intestinal immune system maintains intestinal homeostasis in collaboration with diverse immune cell subsets residing at the epithelial layer, lamina propria and gut-associated lymphoid tissue (GALT). Bacterial components and their metabolites are essential for the establishment of the gut immune system. In addition, nutritional signals contribute to maintaining the mucosal immune response. Specialized epithelial microfold (M) cells in GALT facilitate immune surveillance on the mucosal surface by actively taking up external antigens to transport them into the lymphoid follicles. Because hyperplasia of M cells causes an excessive immune response in GALT, there is a self-regulatory mechanism to control the development of M cells appropriately. In this review, we will discuss the molecular mechanisms of mucosal immune regulation and their biological importance.

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Symbiotic polyamine metabolism regulates epithelial proliferation and macrophage differentiation in the colon

Atsuo Nakamura, Shin Kurihara, Daisuke Takahashi, Wakana Ohashi, Yutaka Nakamura, Shunsuke Kimura, Masayoshi Onuki, Aiko Kume, Yukiko Sasazawa, Yukihiro Furusawa, Yuuki Obata, Shinji Fukuda, Shinji Saiki, Mitsuharu Matsumoto, Koji Hase

Nat Commun （Springer Science and Business Media LLC） 12 （ 1 ） 2105 2021年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2041-1723

<title>Abstract</title>Intestinal microbiota-derived metabolites have biological importance for the host. Polyamines, such as putrescine and spermidine, are produced by the intestinal microbiota and regulate multiple biological processes. Increased colonic luminal polyamines promote longevity in mice. However, no direct evidence has shown that microbial polyamines are incorporated into host cells to regulate cellular responses. Here, we show that microbial polyamines reinforce colonic epithelial proliferation and regulate macrophage differentiation. Colonisation by wild-type, but not polyamine biosynthesis-deficient, <italic>Escherichia coli</italic> in germ-free mice raises intracellular polyamine levels in colonocytes, accelerating epithelial renewal. Commensal bacterium-derived putrescine increases the abundance of anti-inflammatory macrophages in the colon. The bacterial polyamines ameliorate symptoms of dextran sulfate sodium-induced colitis in mice. These effects mainly result from enhanced hypusination of eukaryotic initiation translation factor. We conclude that bacterial putrescine functions as a substrate for symbiotic metabolism and is further absorbed and metabolised by the host, thus helping maintain mucosal homoeostasis in the intestine.

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Identification of Novel Histone Deacetylase 6-Selective Inhibitors Bearing 3,3,3-Trifluorolactic Amide (TFLAM) Motif as a Zinc Binding Group

Takashi Kurohara, Keita Tanaka, Daisuke Takahashi, Satoshi Ueda, Yasunobu Yamashita, Yuri Takada, Hirokazu Takeshima, Shengwang Yu, Yukihiro Itoh, Koji Hase, Takayoshi Suzuki

Chembiochem 16 （ 22 ） 3156 - 3163 2021年07月

研究論文（学術雑誌）, 査読有り, ISSN 1439-4227

Pharmacological inhibition of histone deacetylase 6 (HDAC6) is an effective therapeutic strategy for cancer and immunological diseases. Most of the previously reported HDAC6 inhibitors have a hydroxamate group as a zinc binding group (ZBG), which coordinates to the catalytic zinc ion of HDAC6. The hydroxamate group is liable to metabolically generate mutagenetic hydroxylamine; therefore, non-hydroxamate HDAC6 inhibitors would be advantageous. In this study, to identify novel non-hydroxamate HDAC6-selective inhibitors, screening of a chemical library and the subsequent structural optimization were performed, which led to the identification of HDAC6-selective inhibitors with 3,3,3-trifluorolactic amide (TFLAM) as a novel ZBG. The identified inhibitor showed potent and selective HDAC6-inhibitory activity in cells and induced regulatory T (Treg) cell differentiation.

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Polyamines polarized Th2/Th9 cell-fate decision by regulating GATA3 expression

Atsuo Nakamura, Daisuke Takahashi, Yutaka Nakamura, Takahiro Yamada, Mitsuharu Matsumoto, Koji Hase

Arch Biochem Biophys （Elsevier {BV}） 693 108587 - 108587 2020年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0003-9861

Polyamines produced by both prokaryotes and eukaryotes are bioactive substances with pleiotropic effects. Accumulating evidence has demonstrated that polyamines contribute to anti-inflammatory responses by suppressing the expression of proinflammatory cytokines in mononuclear cells and macrophages. However, the effects of polyamines on CD4+ T cell responses remain to be elucidated. Here, we investigated the effect of polyamines on cell fate decisions of naïve CD4+ T cells in vitro. We found that endogenously generated polyamines are essential for the development of T helper 2 (Th2) cells. Treatment with DL-2-difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, diminished GATA3 expression in CD4+ T cells under Th2-skewed conditions. Supplementation of exogenous polyamines rescued GATA3 downregulation caused by DFMO treatment in CD4+ T cells. Transcriptome analysis revealed that deprivation of endogenous polyamines resulted in upregulated Th9-related genes, such as Il9, Irf4, and Batf3, even under the Th2-skewing conditions. Depletion of intracellular polyamines reduced GATA3 expression but increased IL-9-producing CD4+ T cells under both Th2 and Th9-skewing conditions. Furthermore, oral administration of DFMO increased IL-9-producing CD4+ T cells in small intestine in mice. Thus, our data indicate that polyamines play a critical role in the regulation of the Th2/Th9 balance.

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Microbiota-derived butyrate limits the autoimmune response by promoting the differentiation of follicular regulatory T cells

2020年08月

研究論文（学術雑誌）, 共著, 査読有り

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Microfold cell-dependent antigen transport alleviates infectious colitis by inducing antigen-specific cellular immunity.

Nakamura Y, Mimuro H, Kunisawa J, Furusawa Y, Takahashi D, Fujimura Y, Kaisho T, Kiyono H, Hase K

Mucosal immunology （Springer Science and Business Media LLC） 13 （ 4 ） 679 - 690 2020年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1933-0219

Infectious colitis is one of the most common health issues worldwide. Microfold (M) cells actively transport luminal antigens to gut-associated lymphoid tissue to induce IgA responses; however, it remains unknown whether M cells contribute to the induction of cellular immune responses. Here we report that M cell-dependent antigen transport plays a critical role in the induction of Th1, Th17, and Th22 responses against gut commensals in the steady state. The establishment of commensal-specific cellular immunity was a prerequisite for preventing bacterial dissemination during enteropathogenic Citrobacter rodentium infection. Therefore, M cell-null mice developed severe colitis with increased bacterial dissemination. This abnormality was associated with mucosal barrier dysfunction. These observations suggest that antigen transport by M cells may help maintain gut immune homeostasis by eliciting antigen-specific cellular immune responses.

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Commensal-bacteria-derived butyrate promotes the T-cell-independent IgA response in the colon.

Isobe J, Maeda S, Obata Y, Iizuka K, Nakamura Y, Fujimura Y, Kimizuka T, Hattori K, Kim YG, Morita T, Kimura I, Offermanns S, Adachi T, Nakao A, Kiyono H, Takahashi D, Hase K

International immunology （Oxford University Press） 32 （ 4 ） 243 - 258 2019年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0953-8178

Abstract

Secretory immunoglobulin A (SIgA), the most abundant antibody isotype in the body, maintains a mutual relationship with commensal bacteria and acts as a primary barrier at the mucosal surface. Colonization by commensal bacteria induces an IgA response, at least partly through a T-cell-independent process. However, the mechanism underlying the commensal-bacteria-induced T-cell-independent IgA response has yet to be fully clarified. Here, we show that commensal-bacteria-derived butyrate promotes T-cell-independent IgA class switching recombination (CSR) in the mouse colon. Notably, the butyrate concentration in human stools correlated positively with the amount of IgA. Butyrate up-regulated the production of transforming growth factor β1 and all-trans retinoic acid by CD103+CD11b+ dendritic cells, both of which are critical for T-cell-independent IgA CSR. This effect was mediated by G-protein-coupled receptor 41 (GPR41/FFA3) and GPR109a/HCA2, and the inhibition of histone deacetylase. The butyrate-induced IgA response reinforced the colonic barrier function, preventing systemic bacterial dissemination under inflammatory conditions. These observations demonstrate that commensal-bacteria-derived butyrate contributes to the maintenance of the gut immune homeostasis by facilitating the T-cell-independent IgA response in the colon.

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Fasting-Refeeding Impacts Immune Cell Dynamics and Mucosal Immune Responses

Daisuke Takahashi

Cell （Cell） 178 （ 5 ） 1072 - 1087 2019年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0092-8674

© 2019 Elsevier Inc. Nutritional status potentially influences immune responses; however, how nutritional signals regulate cellular dynamics and functionality remains obscure. Herein, we report that temporary fasting drastically reduces the number of lymphocytes by ∼50% in Peyer's patches (PPs), the inductive site of the gut immune response. Subsequent refeeding seemingly restored the number of lymphocytes, but whose cellular composition was conspicuously altered. A large portion of germinal center and IgA+ B cells were lost via apoptosis during fasting. Meanwhile, naive B cells migrated from PPs to the bone marrow during fasting and then back to PPs during refeeding when stromal cells sensed nutritional signals and upregulated CXCL13 expression to recruit naive B cells. Furthermore, temporal fasting before oral immunization with ovalbumin abolished the induction of antigen-specific IgA, failed to induce oral tolerance, and eventually exacerbated food antigen-induced diarrhea. Thus, nutritional signals are critical in maintaining gut immune homeostasis. Temporary fasting drastically reduces the levels of B cells in Peyer's patches, with germinal center B cells undergoing apoptos

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MZB1 promotes the secretion of J-chain–containing dimeric IgA and is critical for the suppression of gut inflammation

Ermeng Xiong, Yingqian Li, Qing Min, Chaoqun Cui, Jun Liu, Rongjian Hong, Nannan Lai, Ying Wang, Jiping Sun, Ryohtaroh Matsumoto, Daisuke Takahashi, Koji Hase, Reiko Shinkura, Takeshi Tsubata, Ji-Yang W

Proceedings of the National Academy of Sciences of the United States of America （National Academy of Sciences） 116 （ 27 ） 13480 - 13489 2019年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1091-6490

<jats:p>IgA is the most abundantly produced antibody in the body and plays a crucial role in gut homeostasis and mucosal immunity. IgA forms a dimer that covalently associates with the joining (J) chain, which is essential for IgA transport into the mucosa. Here, we demonstrate that the marginal zone B and B-1 cell-specific protein (MZB1) interacts with IgA through the α-heavy-chain tailpiece dependent on the penultimate cysteine residue and prevents the intracellular degradation of α-light-chain complexes. Moreover, MZB1 promotes J-chain binding to IgA and the secretion of dimeric IgA. MZB1-deficient mice are impaired in secreting large amounts of IgA into the gut in response to acute inflammation and develop severe colitis. Oral administration of a monoclonal IgA significantly ameliorated the colitis, accompanied by normalization of the gut microbiota composition. The present study identifies a molecular chaperone that promotes J-chain binding to IgA and reveals an important mechanism that controls the quantity, quality, and function of IgA.</jats:p>

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Sox8 is essential for M cell maturation to accelerate IgA response at the early stage after weaning in mice

Shunsuke Kimura, Nobuhide Kobayashi, Yutaka Nakamura, Takashi Kanaya, Daisuke Takahashi, Ryoji Fujiki, Mami Mutoh, Yuuki Obata, Toshihiko Iwanaga, Tomoo Nakagawa, Naoya Kato, Shintaro Sato, Tsuneyasu Kaisho, Hiroshi Ohno, Koji Hase

Journal of Experimental Medicine （Rockefeller University Press） 216 （ 4 ） 831 - 846 2019年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-1007

Microfold (M) cells residing in the follicle-associated epithelium (FAE) of the gut-associated lymphoid tissue are specialized for antigen uptake to initiate mucosal immune responses. The molecular machinery and biological significance of M cell differentiation, however, remain to be fully elucidated. Here, we demonstrate that Sox8, a member of the SRY-related HMG box transcription factor family, is specifically expressed by M cells in the intestinal epithelium. The expression of Sox8 requires activation of RANKL-RelB signaling. Chromatin immunoprecipitation and luciferase assays revealed that Sox8 directly binds the promoter region of Gp2 to increase Gp2 expression, which is the hallmark of functionally mature M cells. Furthermore, genetic deletion of Sox8 causes a marked decrease in the number of mature M cells, resulting in reduced antigen uptake in Peyer's patches. Consequently, juvenile Sox8-deficient mice showed attenuated germinal center reactions and antigen-specific IgA responses. These findings indicate that Sox8 plays an essential role in the development of M cells to establish mucosal immune responses.

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A partial agonist for retinoid X receptor mitigates experimental colitis

Masayoshi O., Masaki W., Narumi I., Koichiro S., Kei T., Masato H., Takahiro Y., Aiko E., Osamu S., Midori N., Michiko F., Makoto M., Daisuke T., Yukihiro F., Hiroki K., Koji H.

International Immunology （International Immunology） 31 （ 4 ） 251 - 262 2018年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09538178

© The Japanese Society for Immunology. 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is an intractable disease of the gastrointestinal tract. Multiple environmental factors, including food ingredients, have been implicated in the development of these diseases. For example, animal fat-rich diets are predisposing factors for ulcerative colitis, whereas n-3 unsaturated fatty acids such as docosahexaenoic acid (DHA) show protective effects in experimental colitis and are negatively correlated with the incidence of ulcerative colitis and Crohn's disease. Given that DHA exhibits agonistic activity on retinoid X receptor (RXR), activation of RXR could be a therapeutic strategy for IBD. However, conventional full RXR agonists are known to show considerable adverse effects. We therefore took advantage of a partial RXR agonist, CBt-PMN, to minimize the adverse effects, and evaluated its efficacy in dextran sodium sulfate-induced colitis. Administration of CBt-PMN efficiently ameliorated the symptoms of colitis. This effect was attributed to the down-regulation of pro-inflammatory cytokines such as TNF and Il6 in colon-infiltrating monocytes. Down-regulation of pro-inflammatory cytokines by CBt-PMN was also evident in lipopolysaccharide-stimulated bone marrow-derived macrophages (BMDMs). Among many RXR-associated nuclear receptors, activation of peroxisome proliferator-activated receptor δ(PPARd) and nuclear hormone receptor 77 (Nur77) suppressed cytokine production by BMDMs. These observations suggest that the activation of PPARδ/RXR and Nur77/RXR heterodimers by CBt-PMN through the permissive mechanism is responsible for diminishing the monocyte-mediated inflammatory response in the gut. Our data highlight the importance of RXR activation in the regulation of colitis.

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LIGHT-HVEM Signaling in Innate Lymphoid Cell Subsets Protects Against Enteric Bacterial Infection

Daisuke Takahashi

Cell Host & Microbe （Cell Press） 24 （ 2 ） 249 - 260 2018年08月

研究論文（学術雑誌）, 単著, 査読有り, ISSN 1931-3128

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Intestinal epithelial cell-specific deletion of α-mannosidase II ameliorates experimental colitis.

Suzuki K, Yamada T, Yamazaki K, Hirota M, Ishihara N, Sakamoto M, Takahashi D, Iijima H, Hase K

Cell Struct Funct. （Japan Society for Cell Biology） 43 （ 1 ） 25 - 39 2018年01月

研究論文（学術雑誌）, 査読有り, ISSN 1347-3700

Inflammatory bowel disease (IBD) is a refractory disease of the gastrointestinal tract that is believed to develop in genetically susceptible individuals. Glycosylation, a type of post-translational modification, is involved in the development of a wide range of diseases, including IBD, by modulating the function of various glycoproteins. To identify novel genes contributing to the development of IBD, we analyzed single nucleotide polymorphisms (SNPs) of glycosylation-related genes in IBD patients and identified MAN2A1, encoding alphamannosidase II (α-MII), as a candidate gene. α-MII plays a crucial, but not exclusive, role in the maturation of Nglycans. We also observed that intestinal epithelial cells (IECs), which establish the first-line barrier and regulate gut immunity, selectively expressed α-MII with minimal expression of its isozyme, alpha-mannosidase IIx (α-MIIx). This led us to hypothesize that IEC-intrinsic α-MII is implicated in the pathogenesis of IBD. To test this hypothesis, we generated IEC-specific α-MII-deficient (α-MIIΔIEC) mice. Although α-MII deficiency has been shown to have a minimal effect on N-glycan maturation in most cell types due to the compensation by α-MIIx, ablation of α-MII impaired the maturation of N-glycans in IECs. α-MIIΔIEC mice were less susceptible to dextran sulfate sodium-induced colitis compared with control littermates. In accordance with this, neutrophil infiltration in the colonic mucosa was attenuated in α-MIIΔIEC mice. Furthermore, gene expression levels of neutrophilattracting chemokines were downregulated in the colonic tissue. These results suggest that IEC-intrinsic α-MII promotes intestinal inflammation by facilitating chemokine expression. We propose SNPs in MAN2A1 as a novel genetic factor for IBD.

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NALT M cells are important for immune induction for the common mucosal immune system

Yasuhiro Date, Masashi Ebisawa, Shinji Fukuda, Hideaki Shima, Yuuki Obata, Daisuke Takahashi, Tamotsu Kato, Misaho Hanazato, Gaku Nakato, Ifor R Williams, Koji Hase and Hiroshi Ohno

International Immunology （Oxford University Press） 29 （ 10 ） 471 - 478 2017年10月

研究論文（学術雑誌）, 査読有り, ISSN 0953-8178

Nasopharynx-associated lymphoid tissue (NALT) is one of the major constituents of the mucosa-associated lymphoid tissue (MALT), and has the ability to induce antigen-specific immune responses. However, the molecular mechanisms responsible for antigen uptake from the nasal cavity into the NALT remain largely unknown. Immunohistochemical analysis showed that CCL9 and CCL20 were co-localized with glycoprotein 2 (GP2) in the epithelium covering NALT, suggesting the existence of M cells in NALT. In analogy with the reduced number of Peyer's patch M cells in CCR6-deficient mice, the number of NALT M cells was drastically decreased in CCR6-deficient mice compared with the wild-type mice. Translocation of nasally administered Salmonella enterica serovar Typhimurium into NALT via NALT M cells was impaired in CCR6-deficient mice, whereas S. Typhimurium demonstrated consistent co-localization with NALT M cells in wild-type mice. When wild-type mice were nasally administered with an attenuated vaccine strain of S. Typhimurium, the mice were protected from a subsequent challenge with wild-type S. Typhimurium. Antigen-specific fecal and nasal IgA was detected after nasal immunization with the attenuated vaccine strain of S. Typhimurium only in wild-type mice but not in CCR6-deficient mice. Taken together, these observations demonstrate that NALT M cells are important as a first line of defense against infection by enabling activation of the common mucosal immune system (CMIS).

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The epigenetic regulator Uhrf1 facilitates the proliferation and maturation of colonic regulatory T cells

Obata, Yuuki, Furusawa, Yukihiro, Endo, Takaho A., Sharif, Jafar, Takahashi, Daisuke, Atarashi, Koji, Nakayama, Manabu, Onawa, Satoshi, Fujimura, Yumiko, Takahashi, Masumi, Ikawa, Tomokatsu, Otsubo, Takeshi, Kawamura, Yuki I., Dohi, Taeko, Tajima, Shoji, Masumoto, Hiroshi, Ohara, Osamu, Honda, Kenya, Hori, Shohei, Ohno, Hiroshi, Koseki, Haruhiko, Hase, Koji

NATURE IMMUNOLOGY （NATURE PUBLISHING GROUP） 15 （ 6 ） 571 - 579 2014年06月

研究論文（学術雑誌）, 査読有り, ISSN 1529-2908

Intestinal regulatory T cells (T-reg cells) are necessary for the suppression of excessive immune responses to commensal bacteria. However, the molecular machinery that controls the homeostasis of intestinal ireg cells has remained largely unknown. Here we report that colonization of germ-free mice with gut microbiota upregulated expression of the DNA-methylation adaptor Uhrf1 in T-reg cells. Mice with T cell specific deficiency in Uhrf1 (Uhrf1(fl/fl)Cd4-Cre mice) showed defective proliferation and functional maturation of colonic T-reg cells. Uhrf1 deficiency resulted in derepression of the gene (Cdkn1a) that encodes the cyclin-dependent kinase inhibitor p21 due to hypomethylation of its promoter region, which resulted in cell-cycle arrest of T-reg cells. As a consequence, Uhrf1(fl/fl)Cd4-Cre mice spontaneously developed severe colitis. Thus, Uhrf1-dependent epigenetic silencing of Cdknla was required for the maintenance of gut immunological homeostasis. This mechanism enforces symbiotic host-microbe interactions without an inflammatory response.

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Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells (vol 504, pg 446, 2013)

Furusawa, Yukihiro, Obata, Yuuki, Fukuda, Shinji, Endo, Takaho A, Nakato, Gaku, Takahashi, Daisuke, Nakanishi, Yumiko, Uetake, Chikako, Kato, Keiko, Kato, Tamotsu, Takahashi, Masumi, Fukuda, Noriko N, Murakami, Shinnosuke, Miyauchi, Eiji, Hino, Shingo, Atarashi, Koji, Onawa, Satoshi, Fujimura, Yumiko, Locke, Trevor, Clarke, Julie M, Topping, David L, Tomita, Masaru, Hori, Shohei, Ohara, Osamu, Morita, Tatsuya, Koseki, Haruhiko, Kikuchi, Jun, Honda, Kenya, Hase, Koji, Ohno, Hiroshi

NATURE 506 （ 7487 ） 2014年02月

研究論文（学術雑誌）, ISSN 0028-0836

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Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells

Yukihiro Furusawa, Yuuki Obata, Shinji Fukuda, Takaho A. Endo, Gaku Nakato, Daisuke Takahashi, Yumiko Nakanishi, Chikako Uetake, Keiko Kato, Tamotsu Kato, Masumi Takahashi, Noriko N. Fukuda, Shinnosuke Murakami, Eiji Miyauchi, Shingo Hino, Koji Atarashi, Satoshi Onawa, Yumiko Fujimura, Trevor Lockett, Julie M. Clarke, David L. Topping, Masaru Tomita, Shohei Hori, Osamu Ohara, Tatsuya Morita, Haruhiko Koseki, Jun Kikuchi, Kenya Honda, Koji Hase, Hiroshi Ohno

Nature （Springer Science and Business Media LLC） 504 （ 7480 ） 446 - 450 2013年12月

査読有り, ISSN 0028-0836

Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell. Clostridia, a dominant class of commensal microbe, can induce colonic regulatory T (Treg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic Treg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic Treg cells in mice. A comparative NMR-based metabolome analysis suggests that the luminal concentrations of short-chain fatty acids positively correlates with the number of Treg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of Treg cells in vitro and in vivo, and ameliorated the development of colitis induced by adoptive transfer of CD4(+) CD45RB(hi) T cells in Rag1(-/-) mice. Treatment of naive T cells under the Treg-cell-polarizing conditions with butyrate enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus, suggesting a possible mechanism for how microbial-derived butyrate regulates the differentiation of Treg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.

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AP-1B-Mediated Protein Sorting Regulates Polarity and Proliferation of Intestinal Epithelial Cells in Mice

Hase, Koji, Nakatsu, Fubito, Ohmae, Masumi, Sugihara, Kazushi, Shioda, Noriko, Takahashi, Daisuke, Obata, Yuuki, Furusawa, Yukihiro, Fujimura, Yumiko, Yamashita, Taisuke, Fukuda, Shinji, Okamoto, Hiroshi, Asano, Masahide, Yonemura, Shigenobu, Ohno, Hiroshi

GASTROENTEROLOGY 145 （ 3 ） 625 - 635 2013年09月

研究論文（学術雑誌）, 査読有り, ISSN 0016-5085

Background &amp
Aims In epithelial cells, protein sorting mechanisms regulate localization of plasma membrane proteins that generate and maintain cell polarity. The clathrin-adaptor protein (AP) complex AP-1B is expressed specifically in polarized epithelial cells, where it regulates basolateral sorting of membrane proteins. However, little is known about its physiological significance. Methods We analyzed the intestinal epithelia of mice deficient in Ap1m2 (Ap1m2-/- mice), which encodes the AP-1B μ1B subunit, and compared it with 129/B6/CD1 littermates (controls). Notch signaling was inhibited by intraperitoneal injection of dibenzazepine, and β-catenin signaling was inhibited by injection of IWR1. Intestinal tissue samples were collected and analyzed by immunofluorescence analysis. Results Ap1m2 -/- mice developed intestinal epithelial cell hyperplasia. The polarity of intestinal epithelial cells was disrupted, as indicated by the appearance of ectopic microvilli-like structures on the lateral plasma membrane and mislocalization of basolateral membrane proteins, including the low-density lipoprotein receptor and E-cadherin. The E-cadherin-β-catenin complex therefore was disrupted at the adherens junction, resulting in nuclear translocation of β-catenin. This resulted in up-regulation of genes regulated by β-catenin/transcription factor 4 (Tcf4) complex, and increased the proliferation of intestinal epithelial cells. Conclusions AP-1B is required for protein sorting and polarization of intestinal cells in mice. Loss of AP-1B in the intestinal epithelia results in mislocalization of E-cadherin, activation of β-catenin/Tcf4 complex, proliferation, and hyperplasia. © 2013 by the AGA Institute.

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Distinct Roles for CXCR6(+) and CXCR6(-) CD4(+) T Cells in the Pathogenesis of Chronic Colitis

Mandai, Yasushi, Takahashi, Daisuke, Hase, Koji, Obata, Yuuki, Furusawa, Yukihiro, Ebisawa, Masashi, Nakagawa, Tomoo, Sato, Toru, Katsuno, Tatsuro, Saito, Yasushi, Shimaoka, Takeshi, Yokosuka, Osamu, Yokote, Kotaro, Ohno, Hiroshi

PLOS ONE （PUBLIC LIBRARY SCIENCE） 8 （ 6 ） 2013年06月

研究論文（学術雑誌）, 査読有り, ISSN 1932-6203

CD4(+) T cells play a central role in the development of inflammatory bowel disease (IBD) via high-level production of effector cytokines such as IFN-gamma and TNF-alpha. To better characterize the colitogenic CD4(+) T cells, we examined their expression of CXCR6, a chemokine receptor that is expressed by T cells upon activation and is upregulated in several inflammatory diseases. We found that 80% of colonic lamina propria CD4(+) T cells expressed CXCR6 in the CD45RB(high) T cell-transferred colitis model. CXCR6 expression was similarly upregulated in inflamed mucosa of patients with Crohn's disease. Although surface marker analysis demonstrated that both CXCR6(+) and CXCR6(-) CD4(+) T-cell subsets consist of the cells with effector and effector-memory cells, the more cells in the CXCR6(+) subset produced IFN-gamma and TNF-alpha compared to CXCR6(-) subset, and only the CXCR6(+) subset produced IL-17A. Nevertheless, adoptive retransfer of lamina propria CXCR6(+) T cells into Rag1(-/-) recipients failed to induce the disease due to limited expansion of the transferred cells. By contrast, retransfer of CXCR6(-) cells evoked colitis similar to that observed in CD4(+)CD45RB(high) T cell-transferred mice, and resulted in their conversion into CXCR6(+) cells. Collectively, these observations suggest that the CXCR6(+) CD4(+) T-cell subset consists of terminally differentiated effector cells that serve as the major source of effector cytokines in the inflamed tissue, whereas CXCR6(-)CD4(+) T-cell subset serves as a colitogenic memory compartment that retains the ability to proliferate and differentiate into CXCR6(+)CD4(+) T cells.

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The Ets transcription factor Spi-B is essential for the differentiation of intestinal microfold cells

Kanaya, Takashi, Hase, Koji, Takahashi, Daisuke, Fukuda, Shinji, Hoshino, Katsuaki, Sasaki, Izumi, Hemmi, Hiroaki, Knoop, Kathryn A., Kumar, Nachiket, Sato, Mayuko, Katsuno, Tatsuro, Yokosuka, Osamu, Toyooka, Kiminori, Nakai, Kumiko, Sakamoto, Ayako, Kitahara, Yuuki, Jinnohara, Toshi, McSorley, Stephen J., Kaisho, Tsuneyasu, Williams, Ifor R., Ohno, Hiroshi

NATURE IMMUNOLOGY 13 （ 8 ） 729 - + 2012年08月

研究論文（学術雑誌）, 査読有り, ISSN 1529-2908

Intestinal microfold cells (M cells) are an enigmatic lineage of intestinal epithelial cells that initiate mucosal immune responses through the uptake and transcytosis of luminal antigens. The mechanisms of M-cell differentiation are poorly understood, as the rarity of these cells has hampered analysis. Exogenous administration of the cytokine RANKL can synchronously activate M-cell differentiation in mice. Here we show the Ets transcription factor Spi-B was induced early during M-cell differentiation. Absence of Spi-B silenced the expression of various M-cell markers and prevented the differentiation of M cells in mice. The activation of T cells via an oral route was substantially impaired in the intestine of Spi-B-deficient (Spib(-/-)) mice. Our study demonstrates that commitment to the intestinal M-cell lineage requires Spi-B as a candidate master regulator.

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Epithelial Cell-Intrinsic Notch Signaling Plays an Essential Role in the Maintenance of Gut Immune Homeostasis

Obata, Yuuki, Takahashi, Daisuke, Ebisawa, Masashi, Kakiguchi, Kisa, Yonemura, Shigenobu, Jinnohara, Toshi, Kanaya, Takashi, Fujimura, Yumiko, Ohmae, Masumi, Hase, Koji, Ohno, Hiroshi

JOURNAL OF IMMUNOLOGY 188 （ 5 ） 2427 - 2436 2012年03月

研究論文（学術雑誌）, 査読有り, ISSN 0022-1767

Intestinal epithelial cells (IECs) have important functions as the first line of defense against diverse microorganisms on the luminal surface. Impaired integrity of IEC has been implicated in increasing the risk for inflammatory disorders in the gut. Notch signaling plays a critical role in the maintenance of epithelial integrity by regulating the balance of secretory and absorptive cell lineages, and also by facilitating epithelial cell proliferation. We show in this article that mice harboring IEC-specific deletion of Rbpj (RBP-J ΔIEC), a transcription factor that mediates signaling through Notch receptors, spontaneously develop chronic colitis characterized by the accumulation of Th17 cells in colonic lamina propria. Intestinal bacteria are responsible for the development of colitis, because their depletion with antibiotics prevented the development of colitis in RBP-J ΔIEC mice. Furthermore, bacterial translocation was evident in the colonic mucosa of RBP-J ΔIEC mice before the onset of colitis, suggesting attenuated epithelial barrier functions in these mice. Indeed, RBP-J ΔIEC mice displayed increase in intestinal permeability after rectal administration of FITC-dextran. In addition to the defect in physical barrier, loss of Notch signaling led to arrest of epithelial cell turnover caused by downregulation of Hes1, a transcriptional repressor of p27 Kip1 and p57 Kip2. Thus, epithelial cell-intrinsic Notch signaling ensures integrity and homeostasis of IEC, and this mechanism is required for containment of intestinal inflammation. Copyright © 2012 by The American Association of Immunologists, Inc.

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The Epithelia-Specific Membrane Trafficking Factor AP-1B Controls Gut Immune Homeostasis in Mice

Takahashi, Daisuke, Hase, Koji, Kimura, Shunsuke, Nakatsu, Fubito, Ohmae, Masumi, Mandai, Yasushi, Sato, Toru, Date, Yasuhiro, Ebisawa, Masashi, Kato, Tamotsu, Obata, Yuuki, Fukuda, Shinji, Kawamura, Yuki I., Dohi, Taeko, Katsuno, Tatsuro, Yokosuka, Osamu, Waguri, Satoshi, Ohno, Hiroshi

GASTROENTEROLOGY 141 （ 2 ） 621 - 632 2011年08月

研究論文（学術雑誌）, 査読有り, ISSN 0016-5085

Background &amp
Aims: Epithelial cells that cover the intestinal mucosal surface maintain immune homeostasis and tolerance in the gastrointestinal tract. However, little is known about the molecular mechanisms that regulate epithelial immune functions. Epithelial cells are distinct in that they are highly polarized
this polarity is, at least in part, established by the epithelium-specific polarized sorting factor adaptor protein (AP)-1B. We investigated the role of AP-1Bmediated protein sorting in the maintenance of gastrointestinal immune homeostasis. Methods: The role of AP-1B in intestinal immunity was examined in AP-1Bdeficient mice (Ap1m2-/-) by monitoring their phenotypes, intestinal morphology, and epithelial barrier functions. AP-1Bmediated protein sorting was examined in polarized epithelial cells from AP-1B knockdown and Ap1m2-/- mice. Results: Ap1m2-/- mice developed spontaneous chronic colitis, characterized by accumulation of interleukin-17Aproducing, T-helper 17 cells. Deficiency of AP-1B caused epithelial immune dysfunction, such as reduced expression of antimicrobial proteins and impaired secretion of immunoglobulin A. These defects promoted intestinal dysbiosis and increased bacterial translocation within the mucosa. Importantly, AP-1B deficiency led to mistargeting of a subset of basolateral cytokine receptors to the apical plasma membrane in a polarized epithelial cell line and in colonic epithelial cells from mice. AP1M2 expression was reduced significantly in colonic epithelium samples from patients with Crohn's disease. Conclusions: AP-1B is required for proper localization of a subset of cytokine receptors in polarized epithelial cells, which allows them to respond to cytokine signals from underlying lamina propria cells. The AP-1Bmediated protein sorting machinery is required for maintenance of immune homeostasis and prevention of excessive inflammation. © 2011 AGA Institute.

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CCR6(hi)CD11c(int) B cells promote M-cell differentiation in Peyer's patch

Ebisawa, Masashi, Hase, Koji, Takahashi, Daisuke, Kitamura, Hiroshi, Knoop, Kathryn A., Williams, Ifor R., Ohno, Hiroshi

INTERNATIONAL IMMUNOLOGY （Oxford University Press (OUP)） 23 （ 4 ） 261 - 269 2011年04月

研究論文（学術雑誌）, 査読有り, ISSN 0953-8178

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Liposomal glycosphingolipids activate natural killer T cell-mediated immune responses through the endosomal pathway

Inoue, Joe, Ideue, Ryuichi, Takahashi, Daisuke, Kubota, Masahiro, Kumazawa, Yoshio

JOURNAL OF CONTROLLED RELEASE 133 （ 1 ） 18 - 23 2009年01月

研究論文（学術雑誌）, ISSN 0168-3659

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Activation-Induced Cytidine Deaminase Deficiency Causes Organ-Specific Autoimmune Disease

Hase, Koji, Takahashi, Daisuke, Ebisawa, Masashi, Kawano, Sayaka, Itoh, Kikuji, Ohno, Hiroshi

PLOS ONE （PUBLIC LIBRARY SCIENCE） 3 （ 8 ） 2008年08月

研究論文（学術雑誌）, 査読有り, ISSN 1932-6203

Activation-induced cytidine deaminase (AID) expressed by germinal center B cells is a central regulator of somatic hypermutation (SHM) and class switch recombination (CSR). Humans with AID mutations develop not only the autosomal recessive form of hyper-IgM syndrome (HIGM2) associated with B cell hyperplasia, but also autoimmune disorders by unknown mechanisms. We report here that AID(-/-) mice spontaneously develop tertiary lymphoid organs (TLOs) in non-lymphoid tissues including the stomach at around 6 months of age. At a later stage, AID(-/-) mice develop a severe gastritis characterized by loss of gastric glands and epithelial hyperplasia. The disease development was not attenuated even under germ-free (GF) conditions. Gastric autoantigen -specific serum IgM was elevated in AID(-/-) mice, and the serum levels correlated with the gastritis pathological score. Adoptive transfer experiments suggest that autoimmune CD4(+) T cells mediate gastritis development as terminal effector cells. These results suggest that abnormal B-cell expansion due to AID deficiency can drive B-cell autoimmunity, and in turn promote TLO formation, which ultimately leads to the propagation of organ-specific autoimmune effector CD4(+) T cells. Thus, AID plays an important role in the containment of autoimmune diseases by negative regulation of autoreactive B cells.

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