Updated on 2026/06/20

写真a

 
Hirota Keiji
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Professor
Position
Professor
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Degree

  • 医学博士 ( 京都大学 )

Research Interests

  • Autoimmune arthritis

  • Th17 cells

Professional Memberships

  • THE JAPANESE SOCIETY FOR IMMUNOLOGY

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  • International Cytokine and Interferon Society

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Committee Memberships

  • 日本免疫学会   評議員  

    2017.1 - 2030.12   

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    Committee type：Academic society

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Papers

  • Tissue-restricted secondary TCR engagement drives the transition from stem-like to CD200+ Egr2hi arthritogenic Th17 cells. International journal

    Yusuke Takeuchi, Daiya Ohara, Hitomi Watanabe, Yuji Nishimura, Takeshi Iwasaki, Shohei Hori, Hiroshi Kawamoto, Hiroki Kato, Gen Kondoh, Akio Morinobu, Tsuneyo Mimori, Keiji Hirota

    Nature immunology   27 ( 4 )   841 - 853   2026.4

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

    Excessive activation of interleukin-17-producing helper T (TH17) cells can cause autoimmune tissue inflammation. However, how TH17 cells enhance their pathogenicity within target tissues and whether destabilized regulatory T cells contribute to pathogenic TH17 cell populations remain unclear. Using a TH17 cell-dependent autoimmune arthritis model, we demonstrated that TH17 and regulatory T cells did not undergo significant mutual plasticity, based on lineage-tracing and T cell receptor (TCR) repertoire analyses. Single-cell RNA sequencing of joint CD4+ T cells revealed three phenotypically distinct TH17 clusters, ranging from a CD103⁺ Tcf1hi stem-like state to a CD200⁺ Egr2hi highly pathogenic state. The phenotypic transition to the CD200⁺ pathogenic state was not a default progression driven by inflammatory cues, but rather a highly selective process mediated by tissue-restricted secondary TCR engagement within inflamed joints. Our findings delineate the heterogeneity and pathogenic potential of arthritogenic TH17 cells, highlighting secondary autoimmune TCR signaling as a critical regulatory determinant of their developmental trajectories that may serve as a therapeutic target for autoimmune arthritis.

    DOI： 10.1038/s41590-026-02447-0

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  • Pathogenic GM-CSF drives functional diversification of inflammatory macrophages in autoimmune arthritis. International journal

    Hiroki Mukoyama, Yusuke Takeuchi, Daiya Ohara, Yoonha Lee, Hitomi Watanabe, Hiroki Kato, Gen Kondoh, Akio Morinobu, Keiji Hirota

    Science advances   12 ( 13 )   eaec0986   2026.3

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

    Autoimmune T cells orchestrate joint inflammation and pain in concert with synovial macrophages; however, the mechanisms governing the development and functional diversification of these macrophages remain unclear. Using a model of T helper 17 cell (TH17 cell)-mediated autoimmune arthritis, we show that joint-infiltrating Ly6Chi monocytes in response to autoimmune TH17 cells, rather than resident synovial macrophages, are the primary mediators of disease pathogenesis. Granulocyte-macrophage colony-stimulating factor (GM-CSF), a critical component of the pathogenic circuit driven by arthritogenic TH17 cells, does not contribute to monocyte recruitment to the synovium but facilitates their subsequent differentiation into functionally distinct synovial macrophage subsets, thereby amplifying joint inflammation. Single-cell RNA sequencing identified two GM-CSF-dependent subpopulations of pathogenic synovial macrophages-Arginase-1+ and epithelial cell adhesion molecule (EpCAM)+ clusters-both expressing proinflammatory cytokines and matrix metalloproteinases. Notably, EpCAM+ macrophages uniquely express Ccl17, a pronociceptive mediator implicated in arthritic pain. Collectively, these findings delineate a GM-CSF-driven program of macrophage diversification that underpins both joint inflammation and pain, implicating this axis in the chronic activation of inflammatory and nociceptive pathways in autoimmune arthritis.

    DOI： 10.1126/sciadv.aec0986

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  • Regnase-1-mediated regulation of neutrophils modulates SARS-CoV-2 pneumonia.

    Yasuda K, Aoki J, Tanaka K, Shichinohe S, Ono C, Vandenbon A, Ohara D, Muramoto Y, Li S, Motooka D, Watanabe H, Hirota K, Kondoh G, Noda T, Standley DM, Ikehara Y, Okada S, Watanabe T, Matsuura Y, Takeuchi O

    PLoS pathogens   2026.2

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    Publishing type：Research paper (scientific journal)  

    The innate immune response to viral infection needs to be tightly regulated to ensure effective pathogen clearance while avoiding excessive immune activation. During SARS-CoV-2 infection, however, the immune system often fails to elicit appropriate responses, resulting in cytokine-release syndrome in patients with COVID-19. In this study, we show that reduced expression of Regnase-1, an RNase that negatively regulates immune cell activation, confers resistance to infection with the mouse-adapted SARS-CoV-2 MA10 strain. In Regnase-1+/- mice, altered neutrophil function contributed to the amelioration of MA10-induced pneumonia. Single-cell RNA sequencing of lung tissue during MA10 infection revealed four distinct neutrophil subsets, and among these, a subset characterized by an interferon-stimulated gene (ISG) signature was decreased in Regnase-1+/- mice. Furthermore, Regnase-1+/- neutrophils exhibited reduced ISG expression without corresponding changes in proinflammatory gene expression. Regnase-1 was found to repress the expression of Tsc22d3, a gene involved in the negative regulation of interferon responses, through its 3' untranslated region. Collectively, these findings suggest that Regnase-1 attenuates resistance to SARS-CoV-2 MA10 infection by promoting excessive interferon responses in neutrophils.

    DOI： 10.1371/journal.ppat.1013969

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  • Stress-induced glucocorticoids enhance acute inflammation by promoting the differentiation of Th17 cells. International journal

    Akihiro Shimba, Guangwei Cui, Shinya Abe, Keiji Hirota, Eiji Miyauchi, Daichi Takami, Shizue Tani-Ichi, Ryoma Kato, Masaki Tajima, Toru Kanahashi, Masaki Miyazaki, Hans-Reimer Rodewald, Hiroyuki Yoshitomi, Hideki Ueno, Hiroshi Ohno, Koichi Ikuta

    Cell reports   44 ( 8 )   116093 - 116093   2025.8

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

    Stress can trigger acute inflammation by increasing the pro-inflammatory cytokine interleukin (IL)-17 for injury and infection, while inducing the production of the immunosuppressive hormone glucocorticoids (GCs). However, the mechanism through which stress-induced GCs enhance acute inflammation by directly regulating the development of IL-17-producing helper T (Th17) cells remains unclear. Here, we demonstrate that GCs promote Th17 cell differentiation and survival in both mice and humans. Stress-induced GCs augment the expansion of Th17 cells expressing low levels of TCF1, a negative regulator of IL-17 expression. In addition, GCs promote Th17 cell differentiation by enhancing glycolysis. Stress-induced GCs also increase IL-17 production and neutrophil recruitment in the intestine upon bacterial antigen stimulation. Moreover, the expansion of Th17 cells mediated by stress-induced GCs exacerbates acute colitis by promoting IL-17 production and neutrophil recruitment. Thus, stress promotes acute inflammation by enhancing the differentiation of Th17 cells through GCs, which may contribute to self-defense against infections.

    DOI： 10.1016/j.celrep.2025.116093

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  • Type 17 immunity: novel insights into intestinal homeostasis and autoimmune pathogenesis driven by gut-primed T cells Invited Reviewed

    Daiya Ohara, Yusuke Takeuchi, Keiji Hirota

    Cellular & Molecular Immunology   21 ( 11 )   1183 - 1200   2024.10

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    Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

    Abstract

    The IL-23 signaling pathway in both innate and adaptive immune cells is vital for orchestrating type 17 immunity, which is marked by the secretion of signature cytokines such as IL-17, IL-22, and GM-CSF. These proinflammatory mediators play indispensable roles in maintaining intestinal immune equilibrium and mucosal host defense; however, their involvement has also been implicated in the pathogenesis of chronic inflammatory disorders, such as inflammatory bowel diseases and autoimmunity. However, the implications of type 17 immunity across diverse inflammation models are complex. This review provides a comprehensive overview of the multifaceted roles of these cytokines in maintaining gut homeostasis and in perturbing gut barrier integrity, leading to acute and chronic inflammation in various models of gut infection and colitis. Additionally, this review focuses on type 17 immunity interconnecting multiple organs in autoimmune conditions, with a particular emphasis on the pathogenesis of autoimmune arthritis and neuroinflammation driven by T cells primed within the gut microenvironment.

    DOI： 10.1038/s41423-024-01218-x

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    Other Link： https://www.nature.com/articles/s41423-024-01218-x

  • Ca2+-evoked sperm cessation determines embryo number in mammals

    Hitomi Watanabe, Daiya Ohara, Shinichiro Chuma, Yusuke Takeuchi, Tomoatsu Takano, Ami Katanaya, Satohiro Nakao, Akihisa Kaneko, Takatoku Oida, Tatsuya Katsuno, Takuya Uehata, Toru Takeo, Munehiro Okamoto, Keiji Hirota, Gen Kondoh

    2024.9

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    Publisher：Cold spring harbor laboratory  

    Abstract

    In mammals, fertilization takes place followed by fetus development in the maternal body, so the number of fetuses that exceeds the mother’s capacity increases the frequency of stunted growth and stillbirths, while an excessive number of pups increases postnatal stunting and maternal child-rearing stress, which is detrimental to offspring procreation and species maintenance. Therefore, various control mechanisms are thought to be at work to ensure that fertilization occurs in appropriate numbers. Sperm are not capable of fertilization immediately after they are produced in the testis, and must undergo a stepwise activation process including capacitation, hyper motility activation or acrosome reaction before they meet the egg in the oviduct, where fertilization takes place, contributing positively on fertilization, which in turn ensures the number of fetuses for the maintenance of species. In contrast, in this study, we found that a subpopulation of sperm is derived in a Ca2+-dependent manner during the process for sperm to acquire fertility, which may regulate the number of fetuses. When sperm were harvested from the epididymis of mice and activatedin vitro, a subpopulation of sperm emerged from the sperm population in which Lypd4 was expressed on the sperm surface at a ratio up to 30%. The sperm in this subpopulation were rather small in size, more permeable to dyes, and had already ceased motility. We further characterized this sperm population by surface antigen screening using various monoclonal antibodies and found the expression of several proteins, such as CD55, ICOS or Ccr3, specific to this population. The emergence of this sperm population was induced at a concentration of about 4% of Ca2+in body fluids and was independent of capacitation or acrosome reaction, and also apoptotic process. This subpopulation also appeared over time in sperm ejaculated into the female body, accounting for about 50% of the sperm that reached the oviduct in an hour. When this sperm subpopulation was then removed from the entire population using anti-Lypd4 antibody followed byin uteroinsemination, the fertilization rate of the oocytes collected from the oviducts doubled. Such a sperm subpopulation was also observed in macaque monkeys, and removal of this subpopulation increased the egg penetration rate of sperm, suggesting that this sperm subpopulation exists commonly in mammals and that the mother’s acceptable fetal number is adjusted by systematically sterilizing a certain number of sperm.

    DOI： 10.1101/2024.09.16.613169

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  • Aberrant RNA sensing in regulatory T cells causes systemic autoimmunity

    Domnica Luca, Sumin Lee, Keiji Hirota, Yasutaka Okabe, Junji Uehori, Kazushi Izawa, Anna-Lisa Lanz, Verena Schütte, Burcu Sivri, Yuta Tsukamoto, Fabian Hauck, Rayk Behrendt, Axel Roers, Takashi Fujita, Ryuta Nishikomori, Min Ae Lee-Kirsch, Hiroki Kato

    Science Advances   10 ( 9 )   2024.3

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    Publishing type：Research paper (scientific journal)   Publisher：American Association for the Advancement of Science (AAAS)  

    Chronic and aberrant nucleic acid sensing causes type I IFN–driven autoimmune diseases, designated type I interferonopathies. We found a significant reduction of regulatory T cells (T regs ) in patients with type I interferonopathies caused by mutations in ADAR1 or IFIH1 (encoding MDA5). We analyzed the underlying mechanisms using murine models and found that T reg -specific deletion of Adar1 caused peripheral T reg loss and scurfy -like lethal autoimmune disorders. Similarly, knock-in mice with T reg -specific expression of an MDA5 gain-of-function mutant caused apoptosis of peripheral T regs and severe autoimmunity. Moreover, the impact of ADAR1 deficiency on T regs is multifaceted, involving both MDA5 and PKR sensing. Together, our results highlight the dysregulation of T reg homeostasis by intrinsic aberrant RNA sensing as a potential determinant for type I interferonopathies.

    DOI： 10.1126/sciadv.adk0820

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  • Notch2 with retinoic acid license IL-23 expression by intestinal EpCAM+ DCIR2+ cDC2s in mice. International journal

    Daiya Ohara, Yusuke Takeuchi, Hitomi Watanabe, Yoonha Lee, Hiroki Mukoyama, Toshiaki Ohteki, Gen Kondoh, Keiji Hirota

    The Journal of experimental medicine   221 ( 2 )   2024.2

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    Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    Despite the importance of IL-23 in mucosal host defense and disease pathogenesis, the mechanisms regulating the development of IL-23-producing mononuclear phagocytes remain poorly understood. Here, we employed an Il23aVenus reporter strain to investigate the developmental identity and functional regulation of IL-23-producing cells. We showed that flagellin stimulation or Citrobacter rodentium infection led to robust induction of IL-23-producing EpCAM+ DCIR2+ CD103- cDC2s, termed cDCIL23, which was confined to gut-associated lymphoid tissues, including the mesenteric lymph nodes, cryptopatches, and isolated lymphoid follicles. Furthermore, we demonstrated that Notch2 signaling was crucial for the development of EpCAM+ DCIR2+ cDC2s, and the combination of Notch2 signaling with retinoic acid signaling controlled their terminal differentiation into cDCIL23, supporting a two-step model for the development of gut cDCIL23. Our findings provide fundamental insights into the developmental pathways and cellular dynamics of IL-23-producing cDC2s at steady state and during pathogen infection.

    DOI： 10.1084/jem.20230923

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  • Targeting abatacept-resistant T-helper-17 cells by aldehyde dehydrogenase inhibition. International journal

    By Yukiko Tokifuji, Hodaka Hayabuchi, Takashi Sasaki, Mariko Hara-Chikuma, Keiji Hirota, Hayato Takahashi, Masayuki Amagai, Akihiko Yoshimura, Shunsuke Chikuma

    iScience   27 ( 1 )   108646 - 108646   2024.1

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

    IL-17-producing helper T (Th17) cells are long-lived and serve as central effector cells in chronic autoimmune diseases. The underlying mechanisms of Th17 persistence remain unclear. We demonstrated that abatacept, a CD28 antagonist, effectively prevented the development of skin disease in a Th17-dependent experimental autoimmune dermatitis model. Abatacept selectively inhibited the emergence of IL-7R-negative effector-phenotype T cells while allowing the survival and proliferation of IL-7R+ memory-phenotype cells. The surviving IL-7R+ Th17 cells expressed genes associated with alcohol/aldehyde detoxification and showed potential to transdifferentiate into IL-7R-negative effector cells. Inhibiting aldehyde dehydrogenase reduced IL-7R+ Th17 cells in vivo, independently of CD28, and exhibited additive effects when combined with abatacept. Our findings suggest that CD28 blockade prevents inflammation without eliminating persistent memory cells. These remaining memory cells can be targeted by other drugs, such as aldehyde dehydrogenase inhibitors, to limit their survival, thereby facilitating the treatment of chronic autoimmune diseases.

    DOI： 10.1016/j.isci.2023.108646

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  • Identification of Surface Markers and Functional Characterization of Myeloid Derived Suppressor Cell-Like Adherent Cells. International journal

    John Clyde Co Soriano, Shiho Tsutsumi, Daiya Ohara, Keiji Hirota, Gen Kondoh, Tatsuya Niwa, Hideki Taguchi, Tetsuya Kadonosono, Shinae Kizaka-Kondoh

    Advanced biology   e2300159   2023.11

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

    Myeloid-derived suppressor cell (MDSC)-like adherent cells (MLACs) are a recently identified CD11b+ F4/80- myeloid cell subset that can infiltrate tumors early in development and promote their growth. Because of these functions, MLACs play an important role in establishing an immunosuppressive tumor microenvironment (TME). However, the lack of MLAC-specific markers has hampered further characterization of this cell type. This study identifies the gene signature of MLACs by analyzing RNA-sequencing (RNA-seq) and public single-cell RNA-seq data, revealing that MLACs are an independent cell population that are distinct from other intratumoral myeloid cells. After combining proteome analysis of membrane proteins with RNA-seq data, H2-Ab1 and CD11c are indicated as marker proteins that can support the isolation of MLAC subsets from CD11b+ F4/80- myeloid cells by fluorescence-activated cell sorting. The CD11b+ F4/80- H2-Ab1+ and CD11b+ F4/80- CD11c+ MLAC subsets represent approximately half of the MLAC population that is isolated based on their adhesion properties and possess gene signatures and functional properties similar to those of the MLAC population. Additionally, membrane proteome analysis suggests that MLACs express highly heterogeneous surface proteins. This study facilitates an integrated understanding of heterogeneous intratumoral myeloid cells, as well as the molecular and cellular details of the development of an immunosuppressive TME.

    DOI： 10.1002/adbi.202300159

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  • Construction of a T cell receptor signaling range for spontaneous development of autoimmune disease. International journal

    Atsushi Tanaka, Shinji Maeda, Takashi Nomura, Mara Anais Llamas-Covarrubias, Satoshi Tanaka, Lin Jin, Ee Lyn Lim, Hiromasa Morikawa, Yohko Kitagawa, Shuji Akizuki, Yoshinaga Ito, Chihiro Fujimori, Keiji Hirota, Tosei Murase, Motomu Hashimoto, Junichi Higo, Rose Zamoyska, Ryuzo Ueda, Daron M Standley, Noriko Sakaguchi, Shimon Sakaguchi

    The Journal of experimental medicine   220 ( 2 )   2023.2

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    Thymic selection and peripheral activation of conventional T (Tconv) and regulatory T (Treg) cells depend on TCR signaling, whose anomalies are causative of autoimmunity. Here, we expressed in normal mice mutated ZAP-70 molecules with different affinities for the CD3 chains, or wild type ZAP-70 at graded expression levels under tetracycline-inducible control. Both manipulations reduced TCR signaling intensity to various extents and thereby rendered those normally deleted self-reactive thymocytes to become positively selected and form a highly autoimmune TCR repertoire. The signal reduction more profoundly affected Treg development and function because their TCR signaling was further attenuated by Foxp3 that physiologically repressed the expression of TCR-proximal signaling molecules, including ZAP-70, upon TCR stimulation. Consequently, the TCR signaling intensity reduced to a critical range generated pathogenic autoimmune Tconv cells and concurrently impaired Treg development/function, leading to spontaneous occurrence of autoimmune/inflammatory diseases, such as autoimmune arthritis and inflammatory bowel disease. These results provide a general model of how altered TCR signaling evokes autoimmune disease.

    DOI： 10.1084/jem.20220386

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  • Attenuation of regulatory T cell function by type I IFN signaling in an MDA5 gain-of-function mutant mouse model Reviewed

    Sumin Lee, Keiji Hirota, Verena Schuette, Takashi Fujita, Hiroki Kato

    Biochemical and Biophysical Research Communications   629   171 - 175   2022.11

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    Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    DOI： 10.1016/j.bbrc.2022.09.017

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  • Effect of Impaired T Cell Receptor Signaling on the Gut Microbiota in a Mouse Model of Systemic Autoimmunity. International journal

    Mirei Shirakashi, Mikako Maruya, Keiji Hirota, Tatsuaki Tsuruyama, Takashi Matsuo, Ryu Watanabe, Koichi Murata, Masao Tanaka, Hiromu Ito, Hajime Yoshifuji, Koichiro Ohmura, Dirk Elewaut, Shimon Sakaguchi, Sidonia Fagarasan, Tsuneyo Mimori, Motomu Hashimoto

    Arthritis & rheumatology (Hoboken, N.J.)   74 ( 4 )   641 - 653   2022.4

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

    OBJECTIVE: T cell receptor (TCR) signaling abnormalities and gut dysbiosis are thought to be involved in the development of systemic lupus erythematosus (SLE). However, it is not known whether these mechanisms are interrelated. This study was undertaken to explore the impact of defective TCR signaling on microbiota-driven immune responses and the consequent triggering of systemic autoimmunity. METHODS: The responses of B6SKG mice harboring a mutation in ZAP-70 leading to spontaneous development of SLE were evaluated under specific pathogen-free (SPF) and germ-free (GF) conditions. The gut microbiome was analyzed using 16S ribosomal RNA sequencing. Secretory IgA production in the gut and follicular helper T (Tfh) cell development in the spleen and Peyer's patches were analyzed. Interleukin-17 (IL-17)-deficient mice and segmented filamentous bacteria (SFB)-specific TCR-transgenic mice were used to examine the role of IL-17 and thymic selection. RESULTS: SLE development in B6SKG mice was significantly more attenuated under GF conditions than under SPF conditions. The gut microbiota in B6SKG mice was altered, which was associated with the expansion of SFB and consequent development of SLE by driving Th17 cell differentiation, which was in turn blunted by IL-17 deficiency. Notably, although systemic Tfh development and autoantibody IgG response were enhanced, local gut Tfh and IgA responses were impaired. Moreover, experiments in SFB-specific TCR-transgenic mice revealed that this differential response was caused by altered thymic selection of self- and microbiota-reactive TCR because of defective TCR signaling. CONCLUSION: Our findings indicate that defective TCR signaling alters the gut microbiota and promotes systemic autoimmunity by driving Th17 cell differentiation.

    DOI： 10.1002/art.42016

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  • Dispensable roles of Gsdmd and Ripk3 in sustaining IL-1β production and chronic inflammation in Th17-mediated autoimmune arthritis. International journal

    Yusuke Takeuchi, Daiya Ohara, Hitomi Watanabe, Noriko Sakaguchi, Shimon Sakaguchi, Gen Kondoh, Akio Morinobu, Tsuneyo Mimori, Keiji Hirota

    Scientific reports   11 ( 1 )   18679 - 18679   2021.9

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    Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    Programmed necrosis, such as necroptosis and pyroptosis, is a highly pro-inflammatory cellular event that is associated with chronic inflammation. Although there are various triggers of pyroptosis and necroptosis in autoimmune tissue inflammation and subsequent lytic forms of cell death release abundant inflammatory mediators, including damage-associated molecular patterns and IL-1β, capable of amplifying autoimmune Th17 effector functions, it remains largely unclear whether the programs play a crucial role in the pathogenesis of autoimmune arthritis. We herein report that Gasdermin D (Gsdmd) and receptor interacting serine/threonine kinase 3 (Ripk3)-key molecules of pyroptosis and necroptosis, respectively-are upregulated in inflamed synovial tissues, but dispensable for IL-1β production and the development of IL-17-producing T helper (Th17) cell-mediated autoimmune arthritis in SKG mice. Gsdmd-/-, Ripk3-/-, or Gsdmd-/- Ripk3-/- SKG mice showed severe arthritis with expansion of arthritogenic Th17 cells in the draining LNs and inflamed joints, which was comparable to that in wild-type SKG mice. Despite the marked reduction of IL-1β secretion from Gsdmd-/- or Ripk3-/- bone marrow-derived DCs by canonical stimuli, IL-1β levels in the inflamed synovium were not affected in the absence of Gsdmd or Ripk3. Our results revealed that T cell-mediated autoimmune arthritis proceeds independently of the pyroptosis and necroptosis pathways.

    DOI： 10.1038/s41598-021-98145-y

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  • Distinct Foxp3 enhancer elements coordinate development, maintenance, and function of regulatory T cells Reviewed International journal

    Ryoji Kawakami, Yohko Kitagawa, Kelvin Y. Chen, Masaya Arai, Daiya Ohara, Yamami Nakamura, Keiko Yasuda, Motonao Osaki, Norihisa Mikami, Caleb A. Lareau, Hitomi Watanabe, Gen Kondoh, Keiji Hirota, Naganari Ohkura, Shimon Sakaguchi

    Immunity   54 ( 5 )   947 - 961.e8   2021.5

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    The transcription factor Foxp3 plays crucial roles for Treg cell development and function. Conserved non-coding sequences (CNSs) at the Foxp3 locus control Foxp3 transcription, but how they developmentally contribute to Treg cell lineage specification remains obscure. Here, we show that among Foxp3 CNSs, the promoter-upstream CNS0 and the intergenic CNS3, which bind distinct transcription factors, were activated at early stages of thymocyte differentiation prior to Foxp3 promoter activation, with sequential genomic looping bridging these regions and the promoter. While deletion of either CNS0 or CNS3 partially compromised thymic Treg cell generation, deletion of both completely abrogated the generation and impaired the stability of Foxp3 expression in residual Treg cells. As a result, CNS0 and CNS3 double-deleted mice succumbed to lethal systemic autoimmunity and inflammation. Thus, hierarchical and coordinated activation of Foxp3 CNS0 and CNS3 initiates and stabilizes Foxp3 gene expression, thereby crucially controlling Treg cell development, maintenance, and consequently immunological self-tolerance.

    DOI： 10.1016/j.immuni.2021.04.005

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  • Foxp3+ Regulatory T Cells Inhibit CCl4-Induced Liver Inflammation and Fibrosis by Regulating Tissue Cellular Immunity Reviewed International journal

    Yoshinobu Ikeno, Daiya Ohara, Yusuke Takeuchi, Hitomi Watanabe, Gen Kondoh, Kojiro Taura, Shinji Uemoto, Keiji Hirota

    Frontiers in Immunology   11   584048 - 584048   2020.10

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    Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

    Foxp3+ regulatory T (Treg) cells are pivotal in maintaining immunological self-tolerance and tissue homeostasis; however, it remains unclear how tissue Treg cells respond to liver injury and regulate chronic inflammation, which can cause liver fibrosis. We report here that hepatic Treg cells play a critical role in preventing liver pathology by suppressing inflammatory cellular immunity that can promote liver damage and fibrosis. Chronic liver inflammation induced by injections of carbon tetrachloride (CCl4) led to preferential expansion of hepatic Treg cells that prevented liver fibrosis. In contrast, depletion of Treg cells in the CCl4-induced liver fibrosis model exacerbated the severity of liver pathology. Treg depletion unleashed tissue cellular immunity and drove the activation and expansion of the pro-fibrotic IL-4-producing T helper 2 cells, as well as CCR2high Ly-6Chigh inflammatory monocytes/macrophages in the inflamed liver. Although Treg expression of amphiregulin plays a key role in tissue remodeling and repair in various inflammation models, amphiregulin from hepatic Treg cells, the largest producer among liver immune cells, was dispensable for maintaining liver homeostasis and preventing liver fibrosis during CCl4-induced chronic inflammation. Our results indicate that Treg cells control chronic liver inflammation and fibrosis by regulating the aberrant activation and functions of immune effector cells. Harnessing Treg functions, which effectively regulate tissue cellular immunity, may be a therapeutic strategy for preventing and treating liver fibrosis.

    DOI： 10.3389/fimmu.2020.584048

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  • Impaired T cell receptor signaling and development of T cell-mediated autoimmune arthritis. Reviewed International journal

    Yusuke Takeuchi, Keiji Hirota, Shimon Sakaguchi

    Immunological reviews   294 ( 1 )   164 - 176   2020.3

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    Authorship：Corresponding author   Language：English  

    Mutations of the genes encoding T-cell receptor (TCR)-proximal signaling molecules, such as ZAP-70, can be causative of immunological diseases ranging from T-cell immunodeficiency to T-cell-mediated autoimmune disease. For example, SKG mice, which carry a hypomorphic point mutation of the Zap-70 gene, spontaneously develop T-cell-mediated autoimmune arthritis immunopathologically similar to human rheumatoid arthritis (RA). The Zap-70 mutation alters the sensitivity of developing T cells to thymic positive/negative selection by self-peptides/MHC complexes, shifting self-reactive TCR repertoire to include a dominant arthritogenic specificity and also affecting thymic development and function of autoimmune suppressive regulatory T (Treg) cells. Polyclonal self-reactive T cells, including potentially arthritogenic T cells, thus produced by the thymus recognize self-peptide/MHC complexes on antigen-presenting cells (APCs) in the periphery and stimulate them to produce cytokines including IL-6 to drive the arthritogenic T cells to differentiate into arthritogenic T-helper 17 (Th17) cells. Insufficient Treg suppression or activation of APCs via microbial and other environmental stimuli evokes arthritis by activating granulocyte-macrophage colony-stimulating factor-secreting effector Th17 cells, mediating chronic bone-destructive joint inflammation by activating myeloid cells, innate lymphoid cells, and synoviocytes in the joint. These findings obtained from the study of SKG mouse arthritis are instrumental in understanding how arthritogenic T cells are produced, become activated, and differentiate into effector T cells mediating arthritis, and may help devising therapeutic measures targeting autoimmune pathogenic Th17 cells or autoimmune-suppressing Treg cells to treat and prevent RA.

    DOI： 10.1111/imr.12841

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  • Conversion of antigen-specific effector/memory T cells into Foxp3-expressing Treg cells by inhibition of CDK8/19. Reviewed International journal

    Masahiko Akamatsu, Norihisa Mikami, Naganari Ohkura, Ryoji Kawakami, Yohko Kitagawa, Atsushi Sugimoto, Keiji Hirota, Naoto Nakamura, Satoru Ujihara, Toshio Kurosaki, Hisao Hamaguchi, Hironori Harada, Guliang Xia, Yoshiaki Morita, Ichiro Aramori, Shuh Narumiya, Shimon Sakaguchi

    Science immunology   4 ( 40 )   2019.10

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

    A promising way to restrain hazardous immune responses, such as autoimmune disease and allergy, is to convert disease-mediating T cells into immunosuppressive regulatory T (Treg) cells. Here, we show that chemical inhibition of the cyclin-dependent kinase 8 (CDK8) and CDK19, or knockdown/knockout of the CDK8 or CDK19 gene, is able to induce Foxp3, a key transcription factor controlling Treg cell function, in antigen-stimulated effector/memory as well as naïve CD4+ and CD8+ T cells. The induction was associated with STAT5 activation, independent of TGF-β action, and not affected by inflammatory cytokines. Furthermore, in vivo administration of a newly developed CDK8/19 inhibitor along with antigen immunization generated functionally stable antigen-specific Foxp3+ Treg cells, which effectively suppressed skin contact hypersensitivity and autoimmune disease in animal models. The results indicate that CDK8/19 is physiologically repressing Foxp3 expression in activated conventional T cells and that its pharmacological inhibition enables conversion of antigen-specific effector/memory T cells into Foxp3+ Treg cells for the treatment of various immunological diseases.

    DOI： 10.1126/sciimmunol.aaw2707

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  • Synovial Tissue Inflammation Mediated by Autoimmune T Cells Reviewed

    Keiji Hirota

    Frontiers in Immunology   10   1989   2019.8

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    Authorship：Corresponding author   Publishing type：Research paper (scientific journal)  

    DOI： 10.3389/fimmu.2019.01989

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  • Identification of a genomic enhancer that enforces proper apoptosis induction in thymic negative selection. Reviewed International journal

    Miki Arai Hojo, Kyoko Masuda, Hiroaki Hojo, Yosuke Nagahata, Keiko Yasuda, Daiya Ohara, Yusuke Takeuchi, Keiji Hirota, Yutaka Suzuki, Hiroshi Kawamoto, Shinpei Kawaoka

    Nature communications   10 ( 1 )   2603 - 2603   2019.6

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    During thymic negative selection, autoreactive thymocytes carrying T cell receptor (TCR) with overtly strong affinity to self-MHC/self-peptide are removed by Bim-dependent apoptosis, but how Bim is specifically regulated to link TCR activation and apoptosis induction is unclear. Here we identify a murine T cell-specific genomic enhancer EBAB (Bub1-Acoxl-Bim), whose deletion leads to accumulation of thymocytes expressing high affinity TCRs. Consistently, EBAB knockout mice have defective negative selection and fail to delete autoreactive thymocytes in various settings, with this defect accompanied by reduced Bim expression and apoptosis induction. By contrast, EBAB is dispensable for maintaining peripheral T cell homeostasis via Bim-dependent pathways. Our data thus implicate EBAB as an important, developmental stage-specific regulator of Bim expression and apoptosis induction to enforce thymic negative selection and suppress autoimmunity. Our study unravels a part of genomic enhancer codes that underlie complex and context-dependent gene regulation in TCR signaling.

    DOI： 10.1038/s41467-019-10525-1

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  • Correction to: The pathogenicity of Th17 cells in autoimmune diseases. Reviewed

    Yasuda K, Takeuchi Y, Hirota K

    Seminars in immunopathology   41 ( 3 )   299   2019.5

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    DOI： 10.1007/s00281-019-00746-3

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  • The pathogenicity of Th17 cells in autoimmune diseases. Reviewed

    Yasuda K, Takeuchi Y, Hirota K

    Seminars in immunopathology   41 ( 3 )   283 - 297   2019.3

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    DOI： 10.1007/s00281-019-00733-8

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  • Satb1 regulates the effector program of encephalitogenic tissue Th17 cells in chronic inflammation. Reviewed

    Yasuda K, Kitagawa Y, Kawakami R, Isaka Y, Watanabe H, Kondoh G, Kohwi-Shigematsu T, Sakaguchi S, Hirota K

    Nature communications   10 ( 1 )   549   2019.2

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    DOI： 10.1038/s41467-019-08404-w

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  • Autoimmune Th17 Cells Induced Synovial Stromal and Innate Lymphoid Cell Secretion of the Cytokine GM-CSF to Initiate and Augment Autoimmune Arthritis. Reviewed International journal

    Keiji Hirota, Motomu Hashimoto, Yoshinaga Ito, Mayumi Matsuura, Hiromu Ito, Masao Tanaka, Hitomi Watanabe, Gen Kondoh, Atsushi Tanaka, Keiko Yasuda, Manfred Kopf, Alexandre J Potocnik, Brigitta Stockinger, Noriko Sakaguchi, Shimon Sakaguchi

    Immunity   48 ( 6 )   1220 - 1232   2018.6

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    Despite the importance of Th17 cells in autoimmune diseases, it remains unclear how they control other inflammatory cells in autoimmune tissue damage. Using a model of spontaneous autoimmune arthritis, we showed that arthritogenic Th17 cells stimulated fibroblast-like synoviocytes via interleukin-17 (IL-17) to secrete the cytokine GM-CSF and also expanded synovial-resident innate lymphoid cells (ILCs) in inflamed joints. Activated synovial ILCs, which expressed CD25, IL-33Ra, and TLR9, produced abundant GM-CSF upon stimulation by IL-2, IL-33, or CpG DNA. Loss of GM-CSF production by either ILCs or radio-resistant stromal cells prevented Th17 cell-mediated arthritis. GM-CSF production by Th17 cells augmented chronic inflammation but was dispensable for the initiation of arthritis. We showed that GM-CSF-producing ILCs were present in inflamed joints of rheumatoid arthritis patients. Thus, a cellular cascade of autoimmune Th17 cells, ILCs, and stromal cells, via IL-17 and GM-CSF, mediates chronic joint inflammation and can be a target for therapeutic intervention.

    DOI： 10.1016/j.immuni.2018.04.009

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  • Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment (vol 18, pg 173, 2017) Reviewed

    Yohko Kitagawa, Naganari Ohkura, Yujiro Kidani, Alexis Vandenbon, Keiji Hirota, Ryoji Kawakami, Keiko Yasuda, Daisuke Motooka, Shota Nakamura, Motonari Kondo, Ichiro Taniuchi, Terumi Kohwi-Shigematsu, Shimon Sakaguchi

    NATURE IMMUNOLOGY   18 ( 11 )   1270 - 1270   2017.11

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  • Clinical and Histopathological Amelioration of Experimental Autoimmune Encephalomyelitis by AAV Vectors Expressing a Soluble Interleukin-23 Receptor Reviewed

    Marta Miralles, Herena Eixarch, Marcos Tejero, Carme Costa, Keiji Hirota, A. Raul Castano, Meritxell Puig, Gitta Stockinger, Xavier Montalban, Assumpcio Bosch, Carmen Espejo, Miguel Chillon

    NEUROTHERAPEUTICS   14 ( 4 )   1095 - 1106   2017.10

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    DOI： 10.1007/s13311-017-0545-8

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  • Lipid raft dynamics linked to sperm competency for fertilization in mice Reviewed

    Hitomi Watanabe, Rie Takeda, Keiji Hirota, Gen Kondoh

    GENES TO CELLS   22 ( 5 )   493 - 500   2017.5

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    DOI： 10.1111/gtc.12491

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  • Erratum: Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment

    Yohko Kitagawa, Naganari Ohkura, Yujiro Kidani, Alexis Vandenbon, Keiji Hirota, Ryoji Kawakami, Keiko Yasuda, Daisuke Motooka, Shota Nakamura, Motonari Kondo, Ichiro Taniuchi, Terumi Kohwi-Shigematsu, Shimon Sakaguchi

    Nature immunology   18 ( 4 )   474   2017.3

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    DOI： 10.1038/ni0417-474d

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  • Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment Reviewed

    Yohko Kitagawa, Naganari Ohkura, Yujiro Kidani, Alexis Vandenbon, Keiji Hirota, Ryoji Kawakami, Keiko Yasuda, Daisuke Motooka, Shota Nakamura, Motonari Kondo, Ichiro Taniuchi, Terumi Kohwi-Shigematsu, Shimon Sakaguchi

    NATURE IMMUNOLOGY   18 ( 2 )   173 - 183   2017.2

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    DOI： 10.1038/ni.3646

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  • Dysbiosis Contributes to Arthritis Development via Activation of Autoreactive T Cells in the Intestine Reviewed

    Yuichi Maeda, Takashi Kurakawa, Eiji Umemoto, Daisuke Motooka, Yoshinaga Ito, Kazuyoshi Gotoh, Keiji Hirota, Masato Matsushita, Yoki Furuta, Masashi Narazaki, Noriko Sakaguchi, Hisako Kayama, Shota Nakamura, Tetsuya Iida, Yukihiko Saeki, Atsushi Kumanogoh, Shimon Sakaguchi, Kiyoshi Takeda

    ARTHRITIS & RHEUMATOLOGY   68 ( 11 )   2646 - 2661   2016.11

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    DOI： 10.1002/art.39783

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  • Detection of T cell responses to a ubiquitous cellular protein in autoimmune disease Reviewed

    Yoshinaga Ito, Motomu Hashimoto, Keiji Hirota, Naganari Ohkura, Hiromasa Morikawa, Hiroyoshi Nishikawa, Atsushi Tanaka, Moritoshi Furu, Hiromu Ito, Takao Fujii, Takashi Nomura, Sayuri Yamazaki, Akimichi Morita, Dario A. A. Vignali, John W. Kappler, Shuichi Matsuda, Tsuneyo Mimori, Noriko Sakaguchi, Shimon Sakaguchi

    SCIENCE   346 ( 6207 )   363 - 368   2014.10

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    DOI： 10.1126/science.1259077

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  • Activation of the Aryl Hydrocarbon Receptor Dampens the Severity of Inflammatory Skin Conditions Reviewed

    Paola Di Meglio, Joao H. Duarte, Helena Ahlfors, Nick D. L. Owens, Ying Li, Federica Villanova, Isabella Tosi, Keiji Hirota, Frank O. Nestle, Ulrich Mrowietz, Michael J. Gilchrist, Brigitta Stockinger

    IMMUNITY   40 ( 6 )   989 - 1001   2014.6

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    DOI： 10.1016/j.immuni.2014.04.019

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  • Differential Influences of the Aryl Hydrocarbon Receptor on Th17 Mediated Responses in vitro and in vivo Reviewed

    Joao H. Duarte, Paola Di Meglio, Keiji Hirota, Helena Ahlfors, Brigitta Stockinger

    PLOS ONE   8 ( 11 )   e79819   2013.11

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    DOI： 10.1371/journal.pone.0079819

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  • Plasticity of TH 17 cells in Peyer's patches is responsible for the induction of T cell-dependent IgA responses Reviewed

    Keiji Hirota, Jan-Eric Turner, Matteo Villa, João H. Duarte, Jocelyne Demengeot, Oliver M. Steinmetz, Brigitta Stockinger

    Nature Immunology   14 ( 4 )   372 - 379   2013.4

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    DOI： 10.1038/ni.2552

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  • Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3(+)CD25(+)CD4(+) regulatory T cells (vol 202, pg 885, 2005) Reviewed

    Kuibeom Ko, Sayuri Yamazaki, Kyoko Nakamura, Tomohisa Nishioka, Keiji Hirota, Tomoyuki Yamaguchi, Jun Shimizu, Takashi Nomura, Tsutomu Chiba, Shimon Sakaguchi

    JOURNAL OF EXPERIMENTAL MEDICINE   209 ( 2 )   2012.2

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  • Regulation and function of innate and adaptive interleukin-17-producing cells Reviewed

    Keiji Hirota, Helena Ahlfors, Joao H. Duarte, Brigitta Stockinger

    EMBO REPORTS   13 ( 2 )   113 - 120   2012.1

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    DOI： 10.1038/embor.2011.248

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  • An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation Reviewed

    Christoph Wilhelm, Keiji Hirota, Benjamin Stieglitz, Jacques Van Snick, Mauro Tolaini, Katharina Lahl, Tim Sparwasser, Helena Helmby, Brigitta Stockinger

    NATURE IMMUNOLOGY   12 ( 11 )   1071 - U73   2011.11

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    DOI： 10.1038/ni.2133

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  • External influences on the immune system via activation of the aryl hydrocarbon receptor Reviewed

    Brigitta Stockinger, Keiji Hirota, Joao Duarte, Marc Veldhoen

    SEMINARS IN IMMUNOLOGY   23 ( 2 )   99 - 105   2011.4

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  • Fate mapping of IL-17-producing T cells in inflammatory responses Reviewed

    Keiji Hirota, Joao H. Duarte, Marc Veldhoen, Eve Hornsby, Ying Li, Daniel J. Cua, Helena Ahlfors, Christoph Wilhelm, Mauro Tolaini, Ursula Menzel, Anna Garefalaki, Alexandre J. Potocnik, Brigitta Stockinger

    NATURE IMMUNOLOGY   12 ( 3 )   255 - U95   2011.3

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    DOI： 10.1038/ni.1993

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  • Graded Attenuation of TCR Signaling Elicits Distinct Autoimmune Diseases by Altering Thymic T Cell Selection and Regulatory T Cell Function Reviewed

    Satoshi Tanaka, Shinji Maeda, Motomu Hashimoto, Chihiro Fujimori, Yoshinaga Ito, Shin Teradaira, Keiji Hirota, Hiroyuki Yoshitomi, Tomoya Katakai, Akira Shimizu, Takashi Nomura, Noriko Sakaguchi, Shimon Sakaguchi

    JOURNAL OF IMMUNOLOGY   185 ( 4 )   2295 - 2305   2010.8

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    DOI： 10.4049/jimmunol.1000848

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  • Complement drives Th17 cell differentiation and triggers autoimmune arthritis Reviewed

    Motomu Hashimoto, Keiji Hirota, Hiroyuki Yoshitomi, Shinji Maeda, Shin Teradaira, Shuji Akizuki, Paz Prieto-Martin, Takashi Nomura, Noriko Sakaguchi, Joerg Koehl, Birgitta Heyman, Minoru Takahashi, Teizo Fujita, Tsuneyo Mimori, Shimon Sakaguchi

    JOURNAL OF EXPERIMENTAL MEDICINE   207 ( 6 )   1135 - 1143   2010.6

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    DOI： 10.1084/jem.20092301

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  • Development, regulation and functional capacities of Th17 cells Reviewed

    Keiji Hirota, Bruno Martin, Marc Veldhoen

    SEMINARS IN IMMUNOPATHOLOGY   32 ( 1 )   3 - 16   2010.3

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  • Interleukin-17-Producing gamma delta T Cells Selectively Expand in Response to Pathogen Products and Environmental Signals Reviewed

    Bruno Martin, Keiji Hirota, Daniel J. Cua, Brigitta Stockinger, Marc Veldhoen

    IMMUNITY   31 ( 2 )   321 - 330   2009.8

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    DOI： 10.1016/j.immuni.2009.06.020

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  • Modulation of Th17 development and function by activation of the aryl hydrocarbon receptor - the role of endogenous ligands Reviewed

    Brigitta Stockinger, Marc Veldhoen, Keiji Hirota

    EUROPEAN JOURNAL OF IMMUNOLOGY   39 ( 3 )   652 - 654   2009.3

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    DOI： 10.1002/eji.200839134

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  • Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells Reviewed

    Marc Veldhoen, Keiji Hirota, Jillian Christensen, Anne O'Garra, Brigitta Stockinger

    JOURNAL OF EXPERIMENTAL MEDICINE   206 ( 1 )   43 - 49   2009.1

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    DOI： 10.1084/jem.20081438

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  • Arthritis and pneumonitis produced by the same T cell clones from mice with spontaneous autoimmune arthritis Reviewed

    Chiaki Wakasa-Morimoto, Tomoko Toyosaki-Maeda, Takaji Matsutani, Ryu Yoshida, Shino Nakamura-Kikuoka, Miki Maeda-Tanimura, Hiroyuki Yoshitomi, Keiji Hirota, Motomu Hashimoto, Hideyuki Masaki, Yoshiki Fujii, Tsuneaki Sakata, Yuji Tsuruta, Ryuji Suzuki, Noriko Sakaguchi, Shimon Sakaguchi

    INTERNATIONAL IMMUNOLOGY   20 ( 10 )   1331 - 1342   2008.10

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    DOI： 10.1093/intimm/dxn091

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  • The aryl hydrocarbon receptor links T(H)17-cell-mediated autoimmunity to environmental toxins Reviewed

    Marc Veldhoen, Keiji Hirota, Astrid M. Westendorf, Jan Buer, Laure Dumoutier, Jean-Christophe Renauld, Brigitta Stockinger

    NATURE   453 ( 7191 )   106 - +   2008.5

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    DOI： 10.1038/nature06881

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  • Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. Reviewed International journal

    Keiji Hirota, Hiroyuki Yoshitomi, Motomu Hashimoto, Shinji Maeda, Shin Teradaira, Naoshi Sugimoto, Tomoyuki Yamaguchi, Takashi Nomura, Hiromu Ito, Takashi Nakamura, Noriko Sakaguchi, Shimon Sakaguchi

    The Journal of experimental medicine   204 ( 12 )   2803 - 12   2007.11

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    This report shows that interleukin (IL) 17-producing T helper type 17 (Th17) cells predominantly express CC chemokine receptor (CCR) 6 in an animal model of rheumatoid arthritis (RA). Th17 cells induced in vivo in normal mice via homeostatic proliferation similarly express CCR6, whereas those inducible in vitro by transforming growth factor beta and IL-6 additionally need IL-1 and neutralization of interferon (IFN) gamma and IL-4 for CCR6 expression. Forced expression of RORgamma t, a key transcription factor for Th17 cell differentiation, induces not only IL-17 but also CCR6 in naive T cells. Furthermore, Th17 cells produce CCL20, the known ligand for CCR6. Synoviocytes from arthritic joints of mice and humans also produce a large amount of CCL20, with a significant correlation (P = 0.014) between the amounts of IL-17 and CCL20 in RA joints. The CCL20 production by synoviocytes is augmented in vitro by IL-1beta, IL-17, or tumor necrosis factor alpha, and is suppressed by IFN-gamma or IL-4. Administration of blocking anti-CCR6 monoclonal antibody substantially inhibits mouse arthritis. Thus, the joint cytokine milieu formed by T cells and synovial cells controls the production of CCL20 and, consequently, the recruitment of CCR6+ arthritogenic Th17 cells to the inflamed joints. These results indicate that CCR6 expression contributes to Th17 cell function in autoimmune disease, especially in autoimmune arthritis such as RA.

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  • Control of immune responses by antigen-specific regulatory T cells expressing the folate receptor Reviewed

    Tomoyuki Yamaguchi, Keiji Hirota, Kanji Nagahama, Katsuya Ohkawa, Takeshi Takahashi, Takeshi Nomura, Shimon Sakaguchi

    IMMUNITY   27 ( 1 )   145 - 159   2007.7

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    DOI： 10.1016/j.immuni.2007.04.017

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  • T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17(+) Th cells that cause autoimmune arthritis Reviewed

    Keiji Hirota, Motomu Hashimoto, Hiroyuki Yoshitomi, Satoshi Tanaka, Takashi Nomura, Tomoyuki Yamaguchi, Yoichiro Iwakura, Noriko Sakaguchi, Shimon Sakaguchi

    JOURNAL OF EXPERIMENTAL MEDICINE   204 ( 1 )   41 - 47   2007.1

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    DOI： 10.1084/jem.20062259

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  • Foxp3-dependent and -independent molecules specific for CD25(+)CD4(+) natural regulatory T cells revealed by DNA microarray analysis Reviewed

    Naoshi Sugimoto, Takatoku Oida, Keiji Hirota, Kyoko Nakamura, Takashi Nomura, Takashi Uchiyama, Shimon Sakaguchi

    INTERNATIONAL IMMUNOLOGY   18 ( 8 )   1197 - 1209   2006.8

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    DOI： 10.1093/intimm/dx1060

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  • SKG mice, a monogenic model of autoimmune arthritis due to altered signal transduction in T cells. Reviewed

    Sakaguchi S, Takahashi T, Hata H, Yoshitomi H, Tanaka S, Hirota K, Nomura T, Sakaguchi N

    In The hereditary Basis of Rheumatic Diseases, Progress in Inflammation Research. Edited by Rikard Holmdahl, Birkhaeuser Verlag, Basel, p147－159, 2006.   2006

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  • Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3(+)CD25(+)CD4(+) regulatory T cells Reviewed

    K Ko, S Yamazaki, K Nakamura, T Nishioka, K Hirota, T Yamaguchi, J Shimizu, T Nomura, T Chiba, S Sakaguchi

    JOURNAL OF EXPERIMENTAL MEDICINE   202 ( 7 )   885 - 891   2005.10

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    DOI： 10.1084/jem.20050940

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  • A role for fungal beta-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice Reviewed

    H Yoshitomi, N Sakaguchi, K Kobayashi, GD Brown, T Tagami, T Sakihama, K Hirota, S Tanaka, T Nomura, Miki, I, S Gordon, S Akira, T Nakamura, S Sakaguchi

    JOURNAL OF EXPERIMENTAL MEDICINE   201 ( 6 )   949 - 960   2005.3

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    DOI： 10.1084/jem.20051758

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  • Generation of autoaggresive CD4＋ T cells due to a ZAP-70 point mutation in SKG mice that spontaneous develop autoimmune arthritis. Reviewed

    Keiji Hirota, Hiroyuki Yoshitomi, Satoshi Tanaka, Takashi Nomura, Noriko Sakaguchi, Shimon Sakaguchi

    Keystone Symposia Cellular Senescence and Cell Death（2005 3. 3－8. Colorado, USA）   2005

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  • Tumor Immunotherapy with anti GITR monoclonal antibody in mice. Reviewed

    Keiji Hirota, Kwibeom Ko, Sayuri Yamazaki, Jun Shimizu, Kyoko Nakamura, Tomoyuki Yamaguchi, Takashi Nomura, Shimon Sakaguchi

    Keystone Symposia Regulatory/Suppressor T Cells（2004.3.10－15. Banff Canada）   2004

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MISC

  • 腸管IL-23産生細胞の不均一性と機能制御機構

    廣田 圭司

    臨床免疫・アレルギー科   81 ( 6 )   551 - 556   2024.6

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  • 自己免疫疾患に関わるT細胞の制御因子

    小原 乃也, 廣田 圭司

    創薬研究者・アカデミア研究者が知っておくべき最新の免疫学とその応用技術   203 - 213   2021.8

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  • 臨床医が知っておくべき免疫学のいま：PathogenicヘルパーT細胞と組織炎症

    廣田 圭司

    別冊・医学のあゆみ   48 - 53   2021.8

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  • 炎症性Th17細胞による組織炎症の形成

    廣田 圭司

    炎症と免疫   29 ( 5 )   15 - 17   2021.8

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  • PathogenicヘルパーT細胞と組織炎症

    廣田 圭司

    医学のあゆみ   274 ( 12 )   1214 - 1219   2020.9

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  • Th17細胞による関節炎惹起と慢性炎症の維持機構

    廣田 圭司

    リウマチ科、科学評論社   63 ( 6 )   603 - 609   2020.6

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  • 自己免疫性関節炎の発症・慢性化の原因となる炎症ネットワークメカニズムの解明

    廣田 圭司

    医学のあゆみ、医歯薬出版株式会社   269 ( 8 )   603 - 604   2019.5

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  • 新しい解析技術と今後のリウマチ学の発展 関節炎モデルSKGマウスを用いた免疫学的解析

    廣田 圭司

    日本リウマチ学会総会・学術集会プログラム・抄録集   63回   228 - 228   2019.3

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  • 【リンパ球研究の新展開】 自己免疫性関節炎を惹起するTh17細胞を起点とした炎症カスケード

    廣田 圭司

    臨床免疫・アレルギー科   71 ( 1 )   1 - 7   2019.1

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  • Th17細胞の転写制御機構の解明

    廣田 圭司

    上原記念生命科学財団研究報告集   32   1 - 5   2018.12

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  • マウス精子受精能とラフト局在変化の相関性

    渡邊仁美, 竹田理恵, 廣田圭司, 近藤玄

    日本実験動物学会総会講演要旨集   65th   140   2018.4

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  • 慢性肝傷害・肝線維化における制御性T細胞の肝保護効果

    池野嘉信, 廣田圭司, 田浦康二朗, 祝迫惠子, 上本裕介, 吉野健史, 山本玄, 瀬尾智, 海道利実, 上本伸二

    肝臓   59 ( Supplement 1 )   A391   2018.4

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  • マウス精子成熟における遺伝的背景の影響について

    渡邊仁美, 渡邊仁美, 竹田理恵, 竹田理恵, 廣田圭司, 廣田圭司, 近藤玄, 近藤玄

    日本IVF学会雑誌   20 ( 2 )   6‐8   2017.9

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  • 学会印象記(No.117)第45回 日本免疫学会学術集会

    廣田 圭司

    アレルギー・免疫   24 ( 7 )   972 - 974   2017.7

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  • 慢性炎症疾患の新たな展開 慢性炎症と疾患 自己免疫性関節炎を惹起するヘルパーTサブセットと認識自己抗原

    廣田圭司

    最新医学   71   2320‐2325   2016.11

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  • マウス精子成熟における遺伝的背景の影響について

    渡邊仁美, 竹田理恵, 廣田圭司, 近藤玄

    日本IVF学会雑誌   19 ( 2 )   80   2016.9

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  • Inflammatory circuit of Th17 cells, fibroblast-like synoviocytes, and ILCs in the development of autoimmune arthritis

    K. Hirota, Y. Ito, M. Hashimoto, H. Watanabe, G. Kondoh, A. Tanaka, K. Yasuda, M. Kopf, A. J. Potocnik, B. Stockinger, N. Sakaguchi, S. Sakaguchi

    EUROPEAN JOURNAL OF IMMUNOLOGY   46   29 - 29   2016.8

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  • ゲノムオーガナイザーSatb1は制御性T細胞特異的なsuper-enhancerを構築し分化を成立させる

    北川 瑶子, 大倉 永也, 廣田 圭司, 安田 圭子, 近藤 元就, 谷内 一郎, Kohwi-Shigematsu Terumi, 坂口 志文

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   88回・38回   [2T25p - 03(2P0653)]   2015.12

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  • 関節リウマチの病態形成に関与するT細胞クローンの同定と新規自己抗原RPL23A

    廣田圭司, 橋本求, 坂口志文

    感染・炎症・免疫   45 ( 3 )   240‐243 - 70   2015.10

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  • 自然リンパ球の機能と腫瘍形成

    廣田 圭司

    がん免疫療法のメカニズム解明と臨床への展開；がんと免疫、南山堂   37 - 41   2015.10

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  • 自己免疫と免疫寛容にかかわる免疫学の基本 2.Th17細胞の機能制御と自己免疫疾患

    廣田圭司

    実験医学   33 ( 12 )   1877 - 1881   2015.8

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  • 腸管パイエル板におけるIgA産生に関与するT細胞

    廣田 圭司

    臨床免疫・アレルギー科   61 ( 6 )   694 - 699   2014.6

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  • Th17と炎症:最新の知見 Th17細胞のPlasticity(可塑性)

    廣田圭司

    炎症と免疫   21 ( 2 )   93 - 97   2013.2

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  • Plasticity of interleukin 17-producing T cells in inflammatory responses

    Keiji Hirota

    IMMUNOLOGY   136   5 - 5   2012.6

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  • ヘルパーT細胞の分化とサイトカイン 6.ダイオキシン受容体によるTh17細胞の機能制御

    廣田圭司

    実験医学   28 ( 12 )   1910 - 1915   2010.8

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  • Role of aryl hydrocarbon receptor in Th17 function

    廣田 圭司

    Clinical immunology & allergology   53 ( 3 )   235 - 239   2010.3

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  • 補体によるTh‐17依存性自己免疫性関節炎の制御

    橋本求, 廣田圭司, 吉富啓之, 前田伸治, 寺平晋, 秋月修二, PRIETO‐MARTIN Paz, 野村尚史, 坂口教子, 高橋実, 藤田禎三, 三森経世, 坂口志文

    日本免疫学会総会・学術集会記録   39   71 - 71   2009.11

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  • 正常ZAP‐70の発現量操作による自己免疫性関節炎の誘導

    前田伸治, 田中聡, 廣田圭司, 藤森千尋, 野村尚史, 秋月修治, 橋本求, 伊藤能永, 坂口教子, 坂口志文

    日本免疫学会総会・学術集会記録   39   255 - 255   2009.11

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  • 全身性自己免疫疾患 モデル解析 正常ZAP-70の発現量操作による自己免疫性関節炎の誘導

    前田 伸治, 田中 聡, 廣田 圭司, 藤森 千尋, 野村 尚史, 秋月 修治, 橋本 求, 伊藤 能永, 坂口 教子, 坂口 志文

    日本免疫学会総会・学術集会記録   39   255 - 255   2009.11

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  • 関節リウマチ 動物モデル SKGマウスの関節炎発症におけるdectin-1依存的、非依存的な経路の解析

    橋本 求, 廣田 圭司, 吉冨 啓之, 前田 伸治, 寺平 晋, 野村 尚史, 坂口 教子, 岩倉 洋一郎, 三森 経世, 坂口 志文

    日本免疫学会総会・学術集会記録   38   172 - 172   2008.11

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  • SKGマウスの関節炎発症におけるdectin‐1依存的,非依存的な経路の解析

    橋本求, 廣田圭司, 吉冨啓之, 前田伸治, 寺平晋, 野村尚史, 坂口教子, 岩倉洋一郎, 三森経世, 坂口志文

    日本免疫学会総会・学術集会記録   38   172 - 172   2008.11

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  • Rescue of autoimmune arthritis in SKG mice by normalization of TCR signaling transduction

    前田伸治, 田中聡, 廣田圭司, 橋本求, 寺平晋, 秋月修治, 野村尚史, 上田龍三, 坂口教子, 坂口志文

    日本免疫学会総会・学術集会記録   38   247 - 247   2008.11

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  • 全身性自己免疫疾患 モデル TCRシグナル伝達の補正によるSKGマウス自己免疫性関節炎の発症抑制(第2報)

    前田 伸治, 田中 聡, 廣田 圭司, 橋本 求, 寺平 晋, 秋月 修治, 野村 尚史, 上田 龍三, 坂口 教子, 坂口 志文

    日本免疫学会総会・学術集会記録   38   247 - 247   2008.11

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  • 「免疫難病・感染症等の先進医療技術」「制御性T細胞による新しい免疫制御法の開発」TCRシグナル伝達の補正によるSKGマウス自己免疫性関節炎の発症抑制

    前田伸治, 田中聡, 廣田圭司, 橋本求, 寺平晋, 秋月修治, 野村尚史, 上田龍三, 坂口教子, 坂口志文

    免疫難病・感染症等の先進医療技術 第5回(最終)公開シンポジウム要旨集 平成20年   35   2008

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  • SKG マウスの関節炎発症におけるdectine-1 依存的，非依存的な経路の解析/Dectin-1-dependant and - independent pathway for the induction of arthritis in SKG mice Reviewed

    橋本求, 廣田圭司, 吉冨啓之, 前田伸治, 寺平晋, 野村尚史, 坂口教子, 岩倉洋一郎, 三森経世, 坂口志文

    第38回日本免疫学会学術集会（2008.12.1-3． 京都）   2008

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  • 免疫疾患と制御 4.Th17とSKG関節炎

    廣田圭司, 坂口志文

    Annual Review 免疫   2008   273 - 279   2007.11

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  • 自己反応性T細胞のIL‐17産生と環境要因

    橋本求, 廣田圭司, 坂口志文

    月刊臨床免疫・アレルギー科   48 ( 4 )   375 - 378   2007.10

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  • SKGマウスにおける自己反応性CD4+T細胞集団の解析

    寺平晋, 廣田圭司, 橋本求, 前田伸治, 山口智之, 野村尚史, 坂口教子, 坂口志文

    日本免疫学会総会・学術集会記録   37   173 - 173   2007.10

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  • TCRシグナル伝達の補正によるSKGマウス自己免疫性関節炎の発症抑制

    前田伸治, 田中聡, 廣田圭司, 寺平晋, 橋本求, 野村尚史, 上田龍三, 坂口教子, 坂口志文

    日本免疫学会総会・学術集会記録   37   135 - 135   2007.10

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  • SKGマウスにおける自己反応性CD4+T細胞集団の解析

    寺平 晋, 廣田 圭司, 橋本 求, 前田 伸治, 山口 智之, 野村 尚史, 坂口 教子, 坂口 志文

    日本免疫学会総会・学術集会記録   37   173 - 173   2007.10

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  • TCRシグナル伝達の補正によるSKGマウス自己免疫性関節炎の発症抑制

    前田 伸治, 田中 聡, 廣田 圭司, 寺平 晋, 橋本 求, 野村 尚史, 上田 龍三, 坂口 教子, 坂口 志文

    日本免疫学会総会・学術集会記録   37   135 - 135   2007.10

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  • 新しいマーカーFolate receptor 4を発現する抗原特異的CD4+CD25+制御性T細胞による移植免疫寛容の誘導

    長濱寛二, 山口智之, 廣田圭司, 西村英士, 高橋武司, 小川修, 坂口志文

    移植   41   167   2006.9

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  • Foxp3-expressing regulatory T cells in self-tolerance and autoimmune disease

    S. Sakaguchi, N. Sugimoto, M. Ono, T. Oida, K. Hirota, T. Yamaguchi, T. Nomura

    JOURNAL OF NEUROIMMUNOLOGY   178   31 - 32   2006.9

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  • リウマチと骨関節破壊 SKGマウス ZAP-70遺伝子変異による関節リウマチモデルマウス

    坂口 教子, 野村 尚史, 畑 洋, 吉富 啓之, 田中 聡, 廣田 圭司, 坂口 志文

    日本骨代謝学会学術集会プログラム抄録集   24回   105 - 105   2006.7

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  • SKGマウス:ZAP‐70遺伝子変異による関節リウマチモデルマウス

    坂口教子, 野村尚史, 畑洋, 吉富啓之, 田中聡, 廣田圭司, 坂口志文

    日本骨代謝学会学術集会プログラム抄録集   24th   105   2006

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  • 自己免疫性関節炎を自然発症するSKGマウスにおけるCD4+T細胞の自己反応性

    廣田 圭司, 吉富 啓之, 橋本 求, 田中 聡, 野村 尚史, 坂口 教子, 坂口 志文

    日本免疫学会総会・学術集会記録   35   243 - 243   2005.11

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  • CD25+CD4+制御性T細胞によるSKGマウス関節炎の治療

    田中 聡, 橋本 求, 廣田 圭司, 吉富 啓之, 野村 尚史, 坂口 教子, 坂口 志文

    日本免疫学会総会・学術集会記録   35   256 - 256   2005.11

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  • 関節炎を自然発症するSKGマウスにおける抗シトルリン化蛋白抗体産生の検討

    橋本 求, 吉冨 啓之, 田中 聡, 廣田 圭司, 野村 尚史, 坂口 教子, 三森 経世, 坂口 志文

    日本免疫学会総会・学術集会記録   35 ( 0 )   244 - 244   2005.11

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  • 関節炎を自然発症するSKGマウスにおける抗シトルリン化蛋白抗体産生の検討

    橋本 求, 吉冨 啓之, 田中 聡, 廣田 圭司, 野村 尚史, 坂口 教子, 三森 経世, 坂口 志文

    日本臨床免疫学会会誌   28 ( 4 )   264 - 264   2005.8

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  • CD25+CD4+制御性T細胞におけるFoxP3,CTLA-4の役割

    中村 恭子, 廣田 圭司, Fehervari Zoltan, 山口 智之, 野村 尚史, 坂口 志文

    日本免疫学会総会・学術集会記録   34   137 - 137   2004.11

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  • SKGマウスのZAP-70遺伝子突然変異による胸腺T細胞選択の偏倚と,その結果誘導される自己免疫疾患スペクトラムの変化

    田中 聡, 吉富 啓之, 廣田 圭司, 野村 尚史, 坂口 教子, 坂口 志文

    日本免疫学会総会・学術集会記録   34   166 - 166   2004.11

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  • ZAP-70突然変異の結果自己免疫性関節炎を自然発症するSKGマウスの末梢CD4+T細胞動態

    廣田 圭司, 吉富 啓之, 野村 尚史, 坂口 教子, 坂口 志文

    日本免疫学会総会・学術集会記録   34   139 - 139   2004.11

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  • CD25+CD4+制御性T細胞に対するGITRLの役割と腫瘍免疫誘導

    西岡 朋尚, 廣田 圭司, 清水 淳, 坂口 志文

    日本免疫学会総会・学術集会記録   34   137 - 137   2004.11

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  • CD25+CD4+制御性T細胞(Treg)の操作による腫瘍免疫の誘導

    高 貴範, 野村 尚史, 山崎 小百合, 清水 淳, 廣田 圭司, 中村 恭子, 千葉 勉, 坂口 志文

    日本免疫学会総会・学術集会記録   33   114 - 114   2003.11

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  • SKGマウスにおけるiNKT細胞機能解析

    廣田 圭司, Zoltan Fehervari, 吉富 啓之, 野村 尚史, 芹沢 功, 五十嵐 美徳, 若杉 尋, 坂口 教子, 坂口 志文

    日本免疫学会総会・学術集会記録   33   218 - 218   2003.11

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Presentations

  • Terminally differentiated keratinocytes, rather than antigenpresenting cells, provide essential IL-23 in psoriasiform inflammation

    Yoonha Lee, Daiya Ohara, Hiroki Mukoyama, Yusuke Takeuchi, Kazuki Sakatoku, Hitomi Watanabe, Junko Sunaga, Akinori Takaoka, Toshiaki Ohteki, Junji Takeda, Hiroki Kato, Taiji Adachi, Gen Kondoh, Hideo Harigae, Keiji Hirota

    GENE EXPRESSION & SIGNALING IN THE IMMUNE SYSTEM, CSH Meeting, USA  2026.3.6 

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    Event date： 2026.3.4 - 2026.3.8

    Presentation type：Oral presentation (general)  

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  • Gut myeloid cell heterogeneity and environmental cues in the regulation of intestinal homeostasis Invited

    Keiji Hirota

    The 54th Annual Meeting of The Japanese Society for Immunology, Himeji, Japan  2025.12.12 

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    Event date： 2025.12.10 - 2025.12.12

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  • An IL-23 reporter strain reveals the developmental identity and functional regulations of the IL-23-producing gut cDC2s that mediate mucosal host defense against infectious pathogens

    Ohara D, Takeuchi Y, Watanabe H, Lee Y, Mukoyama H, Ohteki T, Kondoh G, Hirota K

    11th Annual Meeting of the International Cytokine & Interferon Society, Athen, Greece  2023.10.18 

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    Event date： 2023.10.15 - 2023.10.18

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  • Foxp3+ regulatory T cells suppress chronic inflammation and fibrosis in the liver by regulating tissue cellular immunity in CCl4-induced liver injury

    Ohara D, Takeuchi Y, Watanabe H, Kondoh G, Hirota K

    2021.12 

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    Event date： 2021.12.8 - 2021.12.10

    Presentation type：Poster presentation  

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  • 自己免疫性関節炎の滑膜組織炎症における炎症性細胞サブセットの役割 Invited

    廣田 圭司

    第38回日本骨代謝学会学術集会  2020.10 

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    Event date： 2020.10.9 - 2020.10.11

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  • Gsdmd and Ripk3 are dispensable for the induction and chronic inflammation of SKG arthritis

    Takeuchi Y, Watanabe H, Kondoh G, Sakaguchi N, Sakaguchi S, Hirota K

    第48回 日本免疫学会学術集会  2019.12.13 

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    Event date： 2019.12.11 - 2019.12.13

    Presentation type：Poster presentation  

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  • A crucial role of the conserved non-coding sequences Foxp3-CNS0 and -CNS3 in the lineage specification of thymic Foxp3+ regulatory T cells

    Kawakami R, Kitagawa Y, Yasuda K, Mikami N, Ohkura N, Watanabe H, Chen K, Kondoh G, Hirota K, Sakaguchi S

    第48回 日本免疫学会学術集会  2019.12.12 

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    Event date： 2019.12.11 - 2019.12.13

    Presentation type：Oral presentation (general)  

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  • Satb1 controls GM-CSF and PD-1 expression by pathogenic Th17 cells

    Hirota K, Yasuda K, Kitagawa Y, Kawakami R, Watanabe H, Kondoh G, Sakaguchi S

    7th Annual Meeting of the International Cytokine & Interferon Society, Oct20-23, 2019, Vienna, Austria  2019.10.21 

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    Event date： 2019.10.20 - 2019.10.23

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  • 胸腺Treg分化におけるFoxp3-CNS0/CNS3領域の重要性

    川上竜司、北川瑶子、Chen K、安田圭子、大倉永也、渡邊仁美、近藤玄、廣田圭司、坂口志文

    Kyoto T Cell Conference 第29回学術集会  2019.6.9 

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    Event date： 2019.6.7 - 2019.6.9

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  • 胸腺における負の選択に特化した機能を持つゲノミックエンハンサーの同定と機能解析

    北條未来、増田喬子、北条広朗、長畑洋佑、安田圭子、小原及也、竹内悠介、廣田圭司、鈴木穣、河本宏、河岡慎平

    Kyoto T Cell Conference 第29回学術集会  2019.6.8 

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    Event date： 2019.6.7 - 2019.6.9

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  • The Genome Organizer Satb1 Regulates GM-CSF and PD-1 Expression in Encephalitogenic Th17 Cells

    Yasuda K, Kitagawa Y, Kawakami R, Isaka Y, Watanabe H, Kondoh G, Kohwi-Shigematsu T, Sakaguchi S, Hirota K

    The 8th NIF Winter School on Advanced Immunology, Singapore  2019.1.21 

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    Event date： 2019.1.20 - 2019.1.23

    Language：English   Presentation type：Oral presentation (general)  

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  • Neutrophil-secreted IL-23 p19 monomer attenuates type 17 immunity

    Daiya Ohara, Kazuki Sakatoku, Hitomi Watanabe, Toshiaki Ohteki, Gen Kondoh, Keiji Hirota

    The 54th Annual Meeting of The Japanese Society for Immunology, Himeji, Japan  2025.12.11 

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  • Identification of an Atypical Keratinocyte Subset as the Primary Source of IL-23 in Psoriatic Skin Inflammation

    Yoonha Lee, Daiya Ohara, Hiroki Mukoyama, Yusuke Takeuchi, Kazuki Sakatoku, Hitomi Watanabe, Akinori Takaoka, Toshiaki Ohteki, Junji Takeda, Gen Kondoh, Hideo Harigae, Keiji Hirota

    Annual Meeting of The Japanese Society for Immunology, Himeji, Japan  2025.12.10 

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  • GM-CSF controls pathogenic function of Ly6Chi monocyte-derived macrophages crucial for synovial inflammation in autoimmune arthritis

    Hiroki Mukoyama, Yusuke Takeuchi, Daiya Ohara, Yoonha Lee, Hitomi Watanabe, Gen Kondoh, Akio Morinobu, Keiji Hirota

    The 54th Annual Meeting of The Japanese Society for Immunology, Himeji, Japan  2025.12.10 

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  • 好中球はIL-23 p19 モノマーを介して17 型免疫応答を抑制する

    小原乃也, 渡邊仁美, 北畠 真, 樗木俊聡, 近藤玄, 廣田圭司

    第34回 Kyoto T Cell Conference, 京都  2025.6.21 

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  • Functional heterogeneity and molecular signature of Inflammatory T helper cells in autoimmune arthritis Invited

    Keiji Hirota

    The 3rd Kyoto University and China Medical University Joint Symposium, Kyoto, Japan  2025.6.21 

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  • Type 17 immunity in health and chronic inflammation Invited

    Keiji Hirota

    Maladaptation at Physiological Barriers: Insights and Outlooks Symposium, Magdeburg, Germany  2025.5.6 

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  • Heterogeneity and molecular basis of arthritogenic Th17 cells in inflamed joints

    Yusuke Takeuchi, Daiya Ohara, Hitomi Watanabe, Gen Kondoh, Akio Morinobu, Keiji, Hirota

    Keystone Symposia: T Cell Differentiation in Tissue Microenvironments, Vancouver, Canada  2025.2.5 

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  • Expression of CD103 and CD200 define functionally distinct arthritogenic Th17 cells

    Yusuke Takeuchi, Daiya Ohara, Hitomi Watanabe, Gen Kondoh, Akio Morinobu, Keiji, Hirota

    The 53rd Annual Meeting of the Japanese Society for Immunology, Nagasaki, Japan  2024.12.4 

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  • GM-CSF-dependent Macrophage Subpopulation Derived from Ly6Chi Monocytes Causes Development and Enhancement of Joint Inflammation in Autoimmune Arthritis

    Hiroki Mukoyama, Yusuke Takeuchi, Daiya Ohara, Yoonha Lee, Hitomi Watanabe, Gen, Kondoh, Akio Morinobu, Keiji Hirota

    The 53rd Annual Meeting of the Japanese Society for Immunology, Nagasaki, Japan  2024.12.4 

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  • Regnase-4 protects mice against HSV-1 infection by reinforcing type I interferon production

    Keiko Yasuda, Junichi Aoki, Kotaro Tanaka, Daiya Ohara, Keiji Hirota, Osamu Takeuchi

    The 53rd Annual Meeting of the Japanese Society for Immunology, Nagasaki, Japan  2024.12.4 

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  • Neutrophil-derived IL-23 p19 monomer suppresses type 17 immunity

    Daiya Ohara, Yusuke Takeuchi, Yoonha Lee, Hiroki Mukoyama, Hitomi Watanabe, Gen Kondoh, Keiji Hirota

    The 53rd Annual Meeting of the Japanese Society for Immunology, Nagasaki, Japan  2024.12.4 

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  • IL-23 secretion by keratinocytes rather than antigen presenting cells play critical role in the pathogenesis of psoriasiform dermatitis

    Yoonha Lee, Daiya Ohara, Hiroki Mukoyama, Yusuke Takeuchi, Hitomi Watanabe, Gen, Kondoh, Keiji Hirota

    The 53rd Annual Meeting of the Japanese Society for Immunology, Nagasaki, Japan  2024.12.4 

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  • Keratinocytes rather than antigen presenting cells are critical source of IL-23 in psoriasiform dermatitis

    Yoonha Lee, Daiya Ohara, Hiroki Mukoyama, Yusuke Takeuchi, Hitomi Watanabe, Gen Kondoh, Keiji Hirota

    Cytokines 2024, 12th Annual Meeting of the International Cytokines & Interferon Society, Korea  2024.10.20 

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  • Novel IL-23 reporter mice reveals the cellular and molecular regulation of IL-23 production in mucosal host defense

    Daiya Ohara, Yusuke Takeuchi, Hitomi Watanabe, Yoonha Lee, Hiroki Mukoyama, Toshiaki Ohteki, Gen Kondoh, Keiji Hirota

    Cytokines 2024, 12th Annual Meeting of the International Cytokines & Interferon Society, Korea  2024.10.20 

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  • A three-stage differentiation pathway for highly arthritogenic CD103- CD200+ Th17 cells

    Yusuke Takeuchi, Daiya Ohara, Hitomi Watanabe, Gen Kondoh, Akio Morinobu, Keiji Hirota

    Cytokines 2024, 12th Annual Meeting of the International Cytokines & Interferon Society, Korea  2024.10.20 

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  • Differentiation and activation of monocytes/macrophages induced by GM-CSF signaling exacerbates synovial inflammation in autoimmune arthritis

    Hiroki Mukoyama, Yusuke Takeuchi, Daiya Ohara, Yoonha Lee, Hitomi Watanabe, Gen Kondoh, Akio Morinobu, Keiji Hirota

    Cytokines 2024, 12th Annual Meeting of the International Cytokines & Interferon Society, Korea  2024.10.20 

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  • Multi-organ Inflammation Driven by Autoimmune Single TCR-bearing T Cells Invited

    Keiji Hirota

    Immunology symposium at The Francis Crick Institute, London, UK  2024.10.11 

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  • Dysregulation of Treg homeostasis by ADAR1 deficiency and chronic MDA5 signaling

    Domnica Luca, Sumin Lee, Keiji Hirota, Yasutaka Okabe, Junji Uehori, Kazushi Izawa, Anna, Lisa Lanz, Verena Schütte, Burcu Sivri, Yuta Tsukamoto, Fabian Hauck, Rayk Behrend, Axel Roers, Takashi Fujita, Ryuta Nishikomori, Min Ae Lee-Kirsch, Hiroki Kato

    The 7th TOLL Conference, Rotterdam, Netherlands  2024.4.18 

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  • GM-CSF-induced differentiation and activation of CCR2+ monocytes in inflamed joints exacerbates synovial inflammation in autoimmune arthritis

    Hiroki Mukoyama, Yusuke Takeuchi, Daiya Ohara, Hitomi Watanabe, Gen, Kondoh, Akio Morinobu, Keiji Hirota

    The 52nd Annual Meeting of the Japanese Society for Immunology, Chiba, Japan  2024.1.18 

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  • Sequential Notch2 and retinoic acid signals liceNotch2 and retinoic acid signals induce IL-23 expression by EpCAM+ DCIR2+ cDC2s in gut-associated lymphoid tissues Invited

    Keiji Hirota

    The 52nd Annual Meeting of the Japanese Society for Immunology, Chiba, Japan  2024.1.18 

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  • Differential TCR affinities for self antigens between Treg and arthritogenic Th17 cells shape the functional imbalance that cause autoimmune arthritis

    Yusuke Takeuchi, Daiya Ohara, Hitomi Watanabe, Gen Kondoh, Akio Morinobu, Keiji Hirota

    The 52nd Annual Meeting of the Japanese Society for Immunology, Chiba, Japan  2024.1.18 

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  • Sequential Notch2 and retinoic acid signals license IL-23 expression by EpCAM+ DCIR2+ CD103- cDC2 in gut-associated lymphoid tissues

    Daiya Ohara, Yusuke Takeuchi, Hitomi Watanabe, Yoonha Lee, Hiroki Mukoyama, Toshiaki Ohteki, Gen Kondoh, Keiji Hirota

    The 52nd Annual Meeting of the Japanese Society for Immunology, Chiba, Japan  2024.1.18 

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  • Differential TCR repertoire for joint self-antigens determines the functional balance between the regulatory T and arthritogenic T cells in T cell-mediated autoimmune arthritis

    Yusuke Takeuchi, Daiya Ohara, Hitomi Watanabe, Gen Kondoh, Akio Morinobu, Keiji Hirota

    2022.12 

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  • An Il23a-Venus reporter strain reveals the spatio-temporal regulation of IL-23- producing cDC2 subset in gut-associated lymphoid tissues

    Daiya Ohara, Hitomi Watanabe, Yusuke Takeuchi, Yoonha LEE, Mukoyama Hiroki, Gen Kondoh, Keiji Hirota

    2022.12 

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  • Regulation and cell fate of CCR2 + inflammatory monocytes in the development of T cell-dependent autoimmune arthritis

    Hiroki Mukoyama, Yusuke Takeuchi, Daiya Ohara, Hitomi Watanabe, Gen Kondoh, Akio Morinobu, Keiji Hirota

    2022.12 

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  • Contribution of T cell receptor- and Interleukin-2- signaling to the coordination of Treg-associated enhancer landscape

    Ryoji Kawakami, Yohko Kitagawa, Kelvin Y. Chen, Masaya Arai, Daiya Ohara, Yamami Nakamura, Keiko Yasuda, Motonao Osaki, Norihisa Mikami, Caleb A. Lareau, Hitomi, Watanabe, Gen Kondoh, Keiji Hirota, Naganari Ohkura, Shimon Sakaguchi

    第50回 日本免疫学会学術集会  2021.12 

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  • 関節炎モデルSKGマウスを用いた免疫学的解析 Invited International conference

    廣田 圭司

    第63回 日本リウマチ学会学術集会  2019.4.16 

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  • 関節炎惹起性T細胞の分化と慢性炎症維持機構 Invited

    廣田 圭司

    「感染・免疫・がん・炎症」シンポジウム  2019.3.27 

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

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  • Inflammatory cascade of autoimmune arthritis by Th17 cells and GM-CSF-producing ILCs International conference

    廣田 圭司

    Keystone symposia  2019.2.20 

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  • 炎症組織の細胞社会学 Invited

    廣田 圭司

    第3回 個体の中の細胞社会学ワークショップ  2019.1.11 

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  • Satb1-mediated regulation of GM-CSF and PD-1 in effector Th17 cells in experimental autoimmune encephalomyelitis International conference

    Yasuda K, Kitagawa Y, Kawakami R, Watanabe H, Kondoh G, Kohwi-Shigematsu T, Sakaguchi S, Hirota K

    第47回 日本免疫学会学術集会  2018.12.10 

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  • A role of Ripk3 and Gsdmd in the development of autoimmune arthritis in SKG mice International conference

    Takeuchi Y, Watanabe H, Kondoh G, Sakaguchi N, Sakaguchi S, Mimori T, Hirota K

    第47回 日本免疫学会学術集会  2018.12.10 

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  • Autoimmune Th17 cells instruct ILC secretion of inflammatory GM-CSF to initiate and augment autoimmune arthritis Invited International conference

    廣田 圭司

    第47回 日本免疫学会学術集会  2018.12.10 

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  • GM-CSF-producing synovial ILCs exacerbate Th17-mediated autoimmune arthritis International conference

    Hirota K, Hashimoto M, Ito Y, Matsuura M, Ito H, Tanaka M, Watanabe H, Kondoh G, Tanaka A, Yasuda K, Kopf M, Potocnik AJ, Stockinger B, Sakaguchi N, Sakaguchi S

    The 3rd International Conference on Innate Lymphoid Cells  2018.11.29 

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  • Satb1-mediated regulation of GM-CSF and PD-1 in pathogenic Th17 cells International conference

    Yasuda K, Kitagawa Y, Kawakami R, Isaka Y, Watanabe H, Kondoh G, Kohwi-Shigematsu T, Sakaguchi S, Hirota K

    6th Annual Meeting of the International Cytokine & Interferon Society  2018.10.27 

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  • Epigenetic landscape of FOXP3 enhancer sites during thymic FOXP3+ TREG development of CNS0- and cNS3-deficient mice International conference

    Kawakami R, Kitagawa Y, Hirota K, Watanabe H, Kondoh G, Ohkura N, Sakaguchi S

    6th Annual Meeting of the International Cytokine & Interferon Society  2018.10.27 

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  • Autoimmune arthritis mediated by inflammatory Th17 cells Invited International conference

    廣田 圭司

    25th East Asia Joint Symposium  2018.10.25 

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  • An inflammatory cellular cascade of autoimmune Th17 cells, GM-CSF-producing synovial ILCs and stromal cells in the development of autoimmune arthritis

    廣田 圭司

    Kyoto T cell Conference  2018.6.15 

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  • Characterization of Innate lymphoid cells in in¬amed gingiva of mice infected with Porphyromonas gingivalis International conference

    Ryoki Kobayashi, Yohei Watanabe, Noriko M Tsuji, Keiji Hirota, Tomoko Kurita-Ochiai

    第46回 日本免疫学会学術集会  2017.12.12 

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  • Lipid raft dynamics linked to sperm competency for fertilization in mice International conference

    Gen Kondoh, Hitomi Watanabe, Rie Takeda, Keiji Hirota

    第4回国際生殖生物学会  2017.9.27 

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  • An inflammatory cellular network of autoimmune Th17 cells, GM-CSF-producing ILCs and synoviocytes in the development of autoimmune arthritis Invited International conference

    廣田 圭司

    Keystone symposia, Immune Regulation in Autoimmunity and Cancer  2017.3.26 

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  • Th17 cells orchestrate an inflammatory circuit in the development of autoimmune arthritis Invited International conference

    廣田 圭司

    World Immune Regulation Meeting X  2016.3.16 

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  • Generation of highly self-reactive T helper cells in SKG autoimmune arthritis Invited International conference

    廣田 圭司

    第１０回 研究所ネットワーク国際シンポジウム  2015.7.23 

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  • T cell-dependent IgA responses by plastic Th17 cells Invited International conference

    廣田 圭司

    IMMUNOLOGY 2014, The American Association of Immunologists Annual Meeeting  2014.5.2 

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  • Function and regulation of autoimmune T helper cells Invited International conference

    廣田 圭司

    The 3rd CSI/JSI/KAI Joint Symposium on Immunology  2013.12.1 

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  • Th17 plasticity in homeostasis and inflammation Invited International conference

    廣田 圭司

    Joint Internatioal Symposium: JSICR-MMCB  2013.5.20 

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  • Plasticity of interleukin 17-producing T cells in inflammatory responses Invited International conference

    廣田 圭司

    Regulatory T cell and T helper cells: Fundamental Biology and Translation Research  2012.3 

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  • Plasticity of interleukin 17-producing T cells in inflammatory responses Invited International conference

    廣田 圭司

    第40回日本免疫学会学術集会  2011.11 

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  • Fate mapping of Interleukin-17 producing T cells in inflammatory responses Invited International conference

    廣田 圭司

    European Thymus Workshop  2011.5 

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  • Contribution of IL-6 to spontaneous differentiation into IL-17-producing arthritogenic T cells in SKG mice Invited International conference

    廣田 圭司

    EULAR Congress 2007  2007.6 

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  • ＳＫＧマウスの関節炎惹起性IL-17産生T細胞の分化におけるIL-6の役割 Invited

    廣田 圭司

    第51回日本リウマチ学会総会  2007.4 

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Industrial property rights

Awards

  • 第4回鈴木衣子賞

    2026.3   大阪市医学会  

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  • リウマチ医学賞

    2025.6   日本リウマチ財団  

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  • 文部科学大臣表彰 若手科学者賞

    2015.4   文部科学省  

    廣田 圭司

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  • 大阪大学総長奨励賞

    2014.7   大阪大学  

    廣田 圭司

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  • 日本免疫学会 第8回研究奨励賞

    2013.12   日本免疫学会  

    廣田 圭司

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Research Projects

  • 炎症性Th17細胞の制御機構と組織炎症の分子基盤

    Grant number：19H01026  2019.04 - 2024.03

    日本学術振興会  科学研究費助成事業 基盤研究(A)  基盤研究(A)

    廣田 圭司

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    Grant amount：\45110000 （ Direct expense: \34700000 、 Indirect expense：\10410000 ）

    本研究課題では自己免疫性関節炎（SKG）モデルを用いて、インターロイキン-17（IL-17）を産生する関節炎惹起性T（Th17）細胞の認識する新規自己抗原を同定し、関節炎局所に局在するTh17細胞と炎症組織細胞による時空間的な相互作用と炎症増幅・慢性化機構の分子基盤を細胞・分子レベルで明らかにする。本年度、同一個体の滑膜組織に共局在するIL-17-eGFP+ Th17細胞とFoxp3+ 制御性T細胞のTCRレパートリー解析を進め、Th17細胞と制御性T細胞間のTCRは重複せず、これら細胞サブセットは炎症組織内で異なった自己抗原を認識することで機能することが示唆された。IL-23産生細胞をシングルセルレベルで解析可能なIL-23-Venusレポーターマウスの作製に成功し、定常状態では腸管粘膜固有層にIL-23産生細胞が常在することを見いだした。
    炎症滑膜組織で炎症の増悪・慢性化を起こす機構の一つとして、細胞死関連プログラムNecroptosis、Pyroptosisに着目したが、T細胞依存性の自己免疫応答にはNecroptosis、Pyroptosis経路は関与しないのみならず、関節炎発症・増悪化に対してNecroptosis、Pyroptosis 経路のクロストークも必要でないことを明らかにし、論文発表をおこなった。

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  • Elucidation of immunological memory of inflammatory T helper cells

    Grant number：17K19553  2017.06 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Research (Exploratory)

    Hirota Keiji

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    Grant amount：\6500000 （ Direct expense: \5000000 、 Indirect expense：\1500000 ）

    In this study, we sought to elucidate the immunological memory formation, and maintenance of autoimmune T cells and a role of memory T cells in the exacerbation of autoimmune diseases. We have established a new reporter system capable of analyzing and separating the interleukin-17 (IL-17)-producing inflammatory T helper (Th17) cell lineage, and found that memory Th17 cells up-regulated pathogenic inflammatory cytokines and induced autoimmune arthritis. We also clarified the tissue distribution between memory Th17 cells and effector Th17 cells, specific differences in cell phenotype and function, and plasticity, and found a novel pathway of effector Th17 cells with disease-causing ability.

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  • A molecular basis of inflammatory Th17 cells in autoimmune diseases

    Grant number：16H06233  2016.04 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (A)

    Hirota Keiji

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    Grant amount：\25090000 （ Direct expense: \19300000 、 Indirect expense：\5790000 ）

    In this study, we investigated an inflammatory cascade mediated by autoimmune Th17 cells and analyzed inflammatory networks starting from Th17 cells and their constituent factors. In particular, we elucidated the significance and regulatory mechanism of GM-CSF-producing inflammatory subsets in autoimmune arthritis, and identified synovial innate lymphoid cells that highly produced GM-CSF, a novel arthritogenic inflammatory subset. We also identified Satb1 as a molecule involved in the regulation of an effector gene expression network in autoimmune Th17 cells. These results advanced our understanding of how chronic inflammation is maintained by the interaction between immune cells and mesenchymal cells.

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  • Molecular basis and therapeutic target for autoimmune arthritis

    Grant number：26253030  2014.04 - 2017.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)  Grant-in-Aid for Scientific Research (A)

    Sakaguchi Shimon

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    Grant amount：\40430000 （ Direct expense: \31100000 、 Indirect expense：\9330000 ）

    In this study, we have developed a new mouse model system with different ZAP-70 functions to understand the development and autoimmune function of T helper cells and identified a particular range of ZAP-70 function associated with the developmental arrest of T cells in the thymus and generation of arthritogenic T helper cells. We have also established a novel retrogenic mouse system to identify auto-antigens recognized by arthritogenic T cells isolated from inflamed joints of SKG mice and demonstrated that T cells specific for the auto-antigen RPL23A induced psoriasis-like skin disease and arthritis. Anti-RPL23A auto-antibody was specific to patients with rheumatoid arthritis, indicating that this screening system for auto-antigens is useful for identifying novel therapeutic targets and new biomarkers for rheumatoid arthritis.

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  • Regulation of GM-CSF-producing Th cells

    Grant number：26670477  2014.04 - 2017.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research  Grant-in-Aid for Challenging Exploratory Research

    Hirota Keiji

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    Grant amount：\3640000 （ Direct expense: \2800000 、 Indirect expense：\840000 ）

    In this study, we identified TNFRSF18 as a specific surface molecule for the regulation of GM-CSF by activated Th cells in vitro. The activation of TNFRSF18 signaling also induced GM-CSF production from effector/memory Th cells in vivo, indicating that this signal cascade is a key molecular pathway to specifically enhance production of GM-CSF. Furthermore, TNFSF18-deficient mice were resistant to the development of experimental autoimmune encephalomyelitis, accompanying impaired production of GM-CSF by tissue infiltrating pathogenic Th cells. Thus, targeting this molecular pathway may be useful for a therapeutic means to prevent or treat the autoimmune disease.

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  • Molecular basis of mucosal immunity maintained by Th17 cells

    Grant number：25713019  2013.04 - 2016.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (A)  Grant-in-Aid for Young Scientists (A)

    HIROTA Keiji

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    Grant amount：\23530000 （ Direct expense: \18100000 、 Indirect expense：\5430000 ）

    Interleukin (IL)-17-producing T helper (Th17) cells play an important role in the maintenance of mucosal immune homeostasis and the host defense against pathogens. In this study, we have established a reporter strain that visualizes IL-17-producing cells and is able to assess their fate. We have studied the regulation and function of Th17 cells and an interaction between Th17 cells and the microbiota in the gut, which controls the constitutive expression of IL-17 and drives production of anti-microbial peptides. We have demonstrated that Th17 cells show plasticity toward T follicular helper cells and help antigen-specific B cells to differentiate into IgA-secreting B cells in the small intestine. Taken together, Th17 cells regulate multiple layers for mucosal immune homeostasis.

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