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大学院医学系研究科（医学専攻等） 医学専攻 病態制御医学系 微生物学講座 |
研究等業績 【 表示 ／ 非表示 】
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Trained innate lymphoid cells in allergic diseases
Ebihara T, Tatematsu M, Fuchimukai A, Yamada T, Yamagata K, Takasuga S, Yamada T
Allergology International 2020年12月 [査読有り] [招待有り]
研究論文（学術雑誌） 国内共著
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Toward Establishing an Ideal Adjuvant for Non-Inflammatory Immune Enhancement.
Tsukasa Seya, Megumi Tatematsu, Misako Matsumoto
Cells 11 ( 24 ) 2022年12月
The vertebrate immune system functions to eliminate invading foreign nucleic acids and foreign proteins from infectious diseases and malignant tumors. Because pathogens and cancer cells have unique amino acid sequences and motifs (e.g., microbe-associated molecular patterns, MAMPs) that are recognized as "non-self" to the host, immune enhancement is one strategy to eliminate invading cells. MAMPs contain nucleic acids specific or characteristic of the microbe and are potential candidates for immunostimulants or adjuvants. Adjuvants are included in many vaccines and are a way to boost immunity by deliberately administering them along with antigens. Although adjuvants are an important component of vaccines, it is difficult to evaluate their efficacy ex vivo and in vivo on their own (without antigens). In addition, inflammation induced by currently candidate adjuvants may cause adverse events, which is a hurdle to their approval as drugs. In addition, the lack of guidelines for evaluating the safety and efficacy of adjuvants in drug discovery research also makes regulatory approval difficult. Viral double-stranded (ds) RNA mimics have been reported as potent adjuvants, but the safety barrier remains unresolved. Here we present ARNAX, a noninflammatory nucleic acid adjuvant that selectively targets Toll-like receptor 3 (TLR3) in antigen-presenting dendritic cells (APCs) to safely induce antigen cross-presentation and subsequently induce an acquired immune response independent of inflammation. This review discusses the challenges faced in the clinical development of novel adjuvants.
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Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes.
Monika I Linder, Yoko Mizoguchi, Sebastian Hesse, Gergely Csaba, Megumi Tatematsu, Marcin Łyszkiewicz, Natalia Zietara, Tim Jeske, Maximilian Hastreiter, Meino Rohlfs, Yanshan Liu, Piotr Grabowski, Kaarin Ahomaa, Daniela Maier-Begandt, Marko Schwestka, Vahid Pazhakh, Abdulsalam Isiaku, Brenda Briones Miranda, Piers Blombery, Megumu K Saito, Ejona Rusha, Zahra Alizadeh, Zahra Pourpak, Masao Kobayashi, Nima Rezaei, Ekrem Unal, Fabian Hauck, Micha Drukker, Barbara Walzog, Juri Rappsilber, Ralf Zimmer, Graham J Lieschke, Christoph Klein
Blood 2022年10月
The mechanisms of coordinated changes in proteome composition and their relevance for the differentiation of neutrophil granulocytes are not well studied. Here, we discover two novel human genetic defects in SRPRA and SRP19, constituents of the mammalian co-translational targeting machinery and characterize their role in neutrophil granulocyte differentiation. We systematically study the proteome of neutrophil granulocytes from patients with variants in the signal recognition particle (SRP) genes, HAX1, and ELANE and identify global as well as specific proteome aberrations. Using in vitro differentiation of human induced pluripotent stem cells and in vivo zebrafish models, we study the effects of SRP-deficiency on neutrophil granulocyte development. In a heterologous cell-based inducible protein expression system, we validate the effects conferred by SRP dysfunction for selected proteins that we identified in our proteome screen. Thus, SRP-dependent protein processing, intracellular trafficking and homeostasis are critically important for the differentiation of neutrophil granulocytes.
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Defects in Signal Recognition Particle (SRP) Components Reveal an Essential and Non-Redundant Role for Granule Biogenesis and Differentiation of Neutrophil Granulocytes
Yoko Mizoguchi, Sebastian Hesse, Monika Linder, Natalia Zietara, Marcin Lyszkiewicz, Yanshan Liu, Megumi Tatematsu, Piotr Grabowski, Kaarin Ahomaa, Tim Jeske, Sebastian Hollizeck, Ejona Rusha, Megumu K. Saito, Masao Kobayashi, Zahra Alizadeh, Zahra Pourpak, Sorin Iurian, Nima Rezaei, Ekrem Unal, Micha Drukker, Barbara Walzog, Fabian Hauck, Juri Rappsilber, Christoph Klein
BLOOD ( AMER SOC HEMATOLOGY ) 134 2019年11月
研究発表要旨（国際会議）
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CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis
Ido Somekh, Marini Thian, David Medgyesi, Nesrin Gülez, Thomas Magg, Alejandro Gallón Duque, Tali Stauber, Atar Lev, Ferah Genel, Ekrem Unal, Amos J. Simon, Yu Nee Lee, Artem Kalinichenko, Jasmin Dmytrus, Michael J. Kraakman, Ginette Schiby, Meino Rohlfs, Jeffrey M. Jacobson, Erdener Özer, Ömer Akcal, Raffaele Conca, Türkan Patiroglu, Musa Karakukcu, Alper Ozcan, Tala Shahin, Eliana Appella, Megumi Tatematsu, Catalina Martinez-Jaramillo, Ivan K. Chinn, Jordan S. Orange, Claudia Milena Trujillo-Vargas, José Luis Franco, Fabian Hauck, Raz Somech, Christoph Klein, Kaan Boztug
Blood ( American Society of Hematology ) 134 ( 18 ) 1510 - 1516 2019年10月
Somekh and colleagues identify CD137, a member of the tumor necrosis factor superfamily, as a novel cause of immunodeficiency associated with a risk of autoimmunity and lymphoid malignancy.
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Extracellular RNA Sensing by Pattern Recognition Receptors.
Megumi Tatematsu, Kenji Funami, Tsukasa Seya, Misako Matsumoto
Journal of innate immunity 10 ( 5-6 ) 398 - 406 2018年
RNA works as a genome and messenger in RNA viruses, and it sends messages in most of the creatures of the Earth, including viruses, bacteria, fungi, plants, and animals. The human innate immune system has evolved to detect single- and double-stranded RNA molecules from microbes by pattern recognition receptors and induce defense reactions against infections such as the production of type I interferons and inflammatory cytokines. To avoid cytokine toxicity causing chronic inflammation or autoimmunity by sensing self-RNA, the activation of RNA sensors is strictly regulated. All of the Toll-like receptors that recognize RNA are localized to endosomes/lysosomes, which require internalization of RNA for sensing through an endocytic pathway. RIG-I-like receptors sense RNA in cytosol. These receptors are expressed in a cell type-specific fashion, enabling sensing of RNA for a wide range of microbial invasions. At the same time, both endosomal and cytoplasmic receptors have strategies to respond only to RNA of pathogenic microorganisms or dying cells. RNA are potential vaccine adjuvants for immune enhancement against cancer and provide a benefit for vaccinations. Understanding the detailed molecular mechanisms of the RNA-sensing system will help us to broaden the clinical utility of RNA adjuvants for patients with incurable diseases.
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Caloric restriction induces cellular quiescence in hepatic ILC1s
Tatematsu M, Fuchimukai A, Nabekura T, Shibuya A, Ebihara T
第 51 回日本免疫学会学術集会 2022年12月 - 2022年12月
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ACTIVATION-INDUCED CELL DEATH OF ILC2 REGULATES CHRONIC ALLERGIC INFLAMMATION
Yamada T, Tatematsu M, Takasuga S, Yamagata K, Shibuya K, Shibuya A, Yamada T, Ebihara T
4th International Conference on Innate Lymphoid Cells 2022年09月 - 2022年09月
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低栄養状態により誘導されるILC1 Quiescence
立松恵, 渕向茜, 海老原敬
第７４回日本細菌学会東北支部会 学術集会・総会 2022年08月 - 2022年08月
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The Ccr4-Not deadenylase complex controls antitumor NK cell activity
Tatematsu M, Sawa S, Ikuta K, Ebihara T
第 50 回日本免疫学会学術集会 2021年12月 - 2021年12月
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The Ccr4-Not deadenylase complex controls antitumor NK cell activity
Megumi Tatematsu, Shinichiro Sawa, Koichi Ikuta, Takashi Ebihara
The 50th Annual Meeting of the Japanese Society for Immunology (奈良) 2021年12月 - 2021年12月 日本免疫学会
NK cells are critical cytotoxic lymphocytesmediating antitumor immune responses. NK cell activity is regulated by posttranslationalmechanisms including mRNA processing, splicing, modification, polyadenylation, andstability. Many miRNAs have been found to modulate NK cell development,maturation, survival, and function by degradation of the target mRNAs. However,mRNA degradation is mainly controlled by poly A deadenylation mediated by the Ccr4-Notdeadenylase complex in mammals. To clarify physiological impact of mRNAstability itself in Group I innate lymphoid cells including NK cells, wedeleted Cnot3, a major functional component of the Ccr4-Not deadenylasecomplex, in ILCs. Absence of Cnot3 led to no differentiation of liver ILC1s andthe reduction in number of splenic NK cells, but almost normal differentiationof ILC1s in the intestine. Cnot3-deficient NK cells exhibited immaturephenotype accompanied by low IFNg responses and low degranulation capability.Furthermore, Cnot3 was required for NK cells to suppress B16F10 tumormetastasis in the lung. We are currently examining how Cnot3 shapes homeostasisof Group I innate lymphoid cells in tissues and regulates antitumor activity ofNK cells.