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Affiliation |
Faculty of Medicine School of Medicine Department of Infectious Diseases, Immunology |
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Associate Professor |
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External Link |
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UTO Tomofumi
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Papers 【 display / non-display 】
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Effect of Hepatic Lipid Overload on Accelerated Hepatocyte Proliferation Promoted by HGF Expression via the SphK1/S1PR2 Pathway in MCD-diet Mouse Partial Hepatectomy Reviewed International coauthorship
Lkham-Erdene Baljinnyam, Choijookhuu Narantsog, Kubota Toshiki, Uto Tomofumi, Mitoma Shuya, Shirouzu Shinichiro, Ishizuka Takumi, Kai Kengo, Higuchi Kazuhiro, Mo Aung Kham, Batmunkh Jargal-Erdene, Sato Katsuaki, Hishikawa Yoshitaka
Acta Histochemica et Cytochemica 57 ( 5 ) 175 - 188 2024.10
Language：English Publishing type：Research paper (scientific journal) Publisher：日本組織細胞化学会
Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming a major health problem worldwide. Liver regeneration is crucial for restoring liver function, and is regulated by extraordinary complex process, involving numerous factors under both physiologic and pathologic conditions. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid synthesized by sphingosine kinase 1 (SphK1), plays an important role in liver function through S1P receptors (S1PRs)-expressing cells. In this study, we investigated the effect of lipid overload on hepatocyte proliferation in a mouse hepatic steatosis model induced by feeding a methionine- and choline-deficient (MCD) diet. After 50% partial hepatectomy (PHx), liver tissues were sampled at various timepoints and then analyzed by immunohistochemistry, oil Red-O staining, quantitative-polymerase chain reaction (qPCR), and flow cytometry. In mice fed the MCD-diet, significantly exacerbated hepatic steatosis and accelerated liver regeneration were observed. After PHx, hepatocyte proliferation peaked at 48 and 36 hr in the liver of chow- and MCD-diet fed mice, respectively. By contrast, increased expression of S1PR2 was observed in hepatic neutrophils and macrophages of MCD-diet fed mice. Flow cytometry and qPCR experiments demonstrated that levels of HGF and FGF2 released by neutrophils and macrophages were significantly higher in MCD-diet fed mice. In conclusion, hepatic lipid overload recruits Kupffer cells and neutrophils that release HGF and FGF2 via SphK1/S1PR2 activation to accelerate hepatocyte proliferation.
DOI： 10.1267/ahc.24-00046
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Crucial role of dendritic cells in the generation of anti-tumor T-cell responses and immunogenic tumor microenvironment to suppress tumor development Reviewed International coauthorship
Tominaga M., Uto T., Fukaya T., Mitoma S., Riethmacher D., Umekita K., Yamashita Y., Sato K.
Frontiers in Immunology 15 1200461 2024.8
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers in Immunology
Dendritic cells (DCs) are known as unique professional antigen (Ag)-presenting cells (APCs) to prime naïve T cells for the initiation of adaptive immunity. While DCs are believed to play a pivotal role in generating anti-tumor T-cell responses, the importance of DCs in the protection from the progression of tumors remains elusive. Here, we show how the constitutive deficiency of CD11chi DCs influences the progression of tumors with the use of binary transgenic mice with constitutive loss of CD11chi DCs. Constitutive loss of CD11chi DCs not only enhances the progression of tumors but also reduces the responses of Ag-specific T cells. Furthermore, the congenital deficiency of CD11chi DCs generates the immunosuppressive tumor microenvironment (TME) that correlates with the marked accumulation of myeloid-derived suppressor cells (MDSCs) and the prominent productions of immunosuppressive mediators. Thus, our findings suggest that CD11chi DCs are crucial for generating anti-tumor T-cell responses and immunogenic TME to suppress the development of tumors.
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Clec4A4 Acts as a Negative Immune Checkpoint Regulator to Suppress Antitumor Immunity Reviewed
Uto T., Fukaya T., Mitoma S., Nishikawa Y., Tominaga M., Choijookhuu N., Hishikawa Y., Sato K.
Cancer Immunology Research 11 ( 9 ) 1266 - 1279 2023.9
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Cancer Immunology Research
Clec4A4 is a C-Type lectin receptor (CLR) exclusively expressed on murine conventional dendritic cells (cDC) to regulate their activation status. However, the functional role of murine Clec4A4 (mClec4A4) in antitumor immunity remains unclear. Here, we show that mClec4A4 serves as a negative immune checkpoint regulator to impair antitumor immune responses. Deficiency of mClec4A4 lead to a reduction in tumor development, accompanied by enhanced antitumor immune responses and amelioration of the immunosuppressive tumor microenvironment (TME) mediated through the enforced activation of cDCs in tumor-bearing mice. Furthermore, antagonistic mAb to human CLEC4A (hCLEC4A), which is the functional orthologue of mClec4A4, exerted protection against established tumors without any apparent signs of immunerelated adverse events in hCLEC4A-Transgenic mice. Thus, our findings highlight the critical role of mClec4A4 expressed on cDCs as a negative immune checkpoint molecule in the control of tumor progression and provide support for hCLEC4A as a potential target for immune checkpoint blockade in tumor immunotherapy.
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Fukaya T., Uto T., Mitoma S., Takagi H., Nishikawa Y., Tominaga M., Choijookhuu N., Hishikawa Y., Sato K.
Cell Reports 42 ( 5 ) 112431 2023.5
Language：English Publishing type：Research paper (scientific journal) Publisher：Cell Reports
While dysbiosis in the gut is implicated in the impaired induction of oral tolerance generated in mesenteric lymph nodes (MesLNs), how dysbiosis affects this process remains unclear. Here, we describe that antibiotic-driven gut dysbiosis causes the dysfunction of CD11c+CD103+ conventional dendritic cells (cDCs) in MesLNs, preventing the establishment of oral tolerance. Deficiency of CD11c+CD103+ cDCs abrogates the generation of regulatory T cells in MesLNs to establish oral tolerance. Antibiotic treatment triggers the intestinal dysbiosis linked to the impaired generation of colony-stimulating factor 2 (Csf2)-producing group 3 innate lymphoid cells (ILC3s) for regulating the tolerogenesis of CD11c+CD103+ cDCs and the reduced expression of tumor necrosis factor (TNF)-like ligand 1A (TL1A) on CD11c+CD103+ cDCs for generating Csf2-producing ILC3s. Thus, antibiotic-driven intestinal dysbiosis leads to the breakdown of crosstalk between CD11c+CD103+ cDCs and ILC3s for maintaining the tolerogenesis of CD11c+CD103+ cDCs in MesLNs, responsible for the failed establishment of oral tolerance.
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Mechanism on antigen delivery under mucosal vaccination using cell-penetrating peptides immobilized at multiple points on polymeric platforms. Reviewed
Ukawa M, Endo R, Yagi H, Tomono T, Miyata K, Shigeno K, Tobita E, Uto T, Baba M, Sakuma S
International journal of pharmaceutics 613 121376 2022.2
Language：English Publishing type：Research paper (scientific journal)
Books 【 display / non-display 】
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Current Topics in Microbiology and Immunology
Sato, K. Uto, T., Fukaya, T., and Takagi, H.（ Role： Joint author）
Springer Publishing 2017.9
Total pages：47-71 Language：English Book type：Scholarly book
Dendritic cells (DCs) comprise heterogeneous subsets, functionally classified into conventional DCs (cDCs) and plasmacytoid DCs (pDCs). DCs are considered to be essential antigen (Ag)-presenting cells (APCs) that play crucial roles in activation and fine-tuning of innate and adaptive immunity under inflammatory conditions, as well as induction of immune tolerance to maintain immune homeostasis under steady-state conditions. Furthermore, DC functions can be modified and influenced by stimulation with various extrinsic factors, such as ligands for pattern-recognition receptors (PRRs) and cytokines. On the other hand, treatment of DCs with certain immunosuppressive drugs and molecules leads to the generation of tolerogenic DCs that show downregulation of both the major histocompatibility complex (MHC) and costimulatory molecules, and not only show defective T-cell activation, but also possess tolerogenic properties including the induction of anergic T-cells and regulatory T (Treg) cells. To develop an effective strategy for Ag-specific intervention of T-cell-mediated immune disorders, we have previously established the modified DCs with moderately high levels of MHC molecules that are defective in the expression of costimulatory molecules that had a greater immunoregulatory property than classical tolerogenic DCs, which we therefore designated as regulatory DCs (DCreg). Herein, we integrate the current understanding of the role of DCs in the control of immune responses, and further provide new information of the characteristics of tolerogenic DCs and DCreg, as well as their regulation of immune responses and disorders.
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Fukaya, T., Takagi, H., Uto, T, Arimura, K., and Sato, K.（ Role： Joint author）
Springer Publishing 2016.5
Total pages：291-308 Responsible for pages：291-308 Language：English Book type：Scholarly book
MISC 【 display / non-display 】
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樹状細胞のはたらき 7 がん免疫応答における通常型樹状細胞の役割 Invited Reviewed
宇都倫史, 深谷知宏, 三苫修也, 佐藤克明
獣医免疫アレルギー学専門誌 Veterinary Immunology for Practitioners, VIP 36 46 - 51 2024.10
Authorship：Lead author Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (scientific journal)
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樹状細胞のはたらき 6 アレルギー疾患に対する舌下免疫療法の防御効果における樹状細胞の役割 Invited Reviewed
深谷知宏, 宇都倫史, 三苫修也, 佐藤克明
獣医免疫アレルギー学専門誌 Veterinary Immunology for Practitioners, VIP 35 44 - 49 2024.7
Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (scientific journal)
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樹状細胞のはたらき 5 幼若期での抗生剤服用による消化管細菌叢異常に基づく経口免疫寛容の破綻における通常型樹状細胞の役割 Invited Reviewed
深谷知宏, 宇都倫史, 三苫修也, 佐藤克明
獣医免疫アレルギー学専門誌 Veterinary Immunology for Practitioners, VIP 34 15 - 21 2024.4
Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (scientific journal)
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樹状細胞のはたらき 4 経口免疫寛容の誘導における形質細胞様樹状細胞の役割 Invited Reviewed
深谷知宏, 宇都倫史, 三苫修也, 佐藤克明
獣医免疫アレルギー学専門誌 Veterinary Immunology for Practitioners, VIP 33 2 - 6 2024.1
Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (scientific journal)
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樹状細胞のはたらき３ 樹状細胞による制御性T細胞の制御 Invited Reviewed
深谷知宏, 宇都倫史, 三苫修也, 佐藤克明
獣医免疫アレルギー学専門誌 Veterinary Immunology for Practitioners, VIP 32 42 - 47 2023.10
Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (scientific journal)
Presentations 【 display / non-display 】
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Clec4A4 acts as a negative immune checkpoint regulator to suppress antitumor immunity Invited International conference
Uto T., Sato K.
2nd Edition of the Global Meeting on Cancer Research and Therapy (GMCRT-2024) 2024.9.18
Event date： 2024.9.18
Language：English Presentation type：Oral presentation (invited, special)
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高度免疫不全マウスを用いた牛伝染性リンパ腫担がんマウスモデル及び牛免疫細胞移植マウスモデルの作製と有用性の検討
三苫 修也、宇都 倫史、深谷 知宏、冨永 萌、関口 敏、佐藤 克明
第167回日本獣医学会学術集会 2024.9.10
Event date： 2024.9.10 - 2024.9.13
Language：Japanese Presentation type：Oral presentation (general)
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Clec4A4 serves as a negative immune checkpoint regulator expressed on conventional dendritic cells to impair antitumor immunity International conference
Uto T., Fukaya T., Mitoma S., Tominaga M., Sato K.
第52回日本免疫学会学術集会 2024.1.18
Event date： 2024.1.17 - 2024.1.19
Language：English Presentation type：Poster presentation
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Selective cell stimulation with bovine interleukin-2 mutein and the distribution of bovine CD122 on the peripheral lymphocytes International conference
Mitoma S., Uto T., Fukaya T., Tominaga M., Sato K., Norimine J.
第52回日本免疫学会学術集会 2024.1.17
Event date： 2024.1.17 - 2024.1.19
Language：English Presentation type：Poster presentation
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Gut dysbiosis abrogates the establishment of oral tolerance mediated through dysfunction of mucosal dendritic cells International conference
Fukaya T., Uto T., Mitoma S., Tominaga M., Sato K.
第52回日本免疫学会学術集会 2024.1.17
Event date： 2024.1.17 - 2024.1.19
Language：English Presentation type：Poster presentation
Grant-in-Aid for Scientific Research 【 display / non-display 】
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新規ヒト樹状細胞発現免疫チェックポイント分子を標的とした阻害剤の開発
Grant number：23H02773 2023.04 - 2026.03
独立行政法人日本学術振興会 科学研究費助成事業 基盤研究(B)
Authorship：Principal investigator
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ヒト樹状細胞を標的とした新規免疫チェックポイント阻害剤の開発
Grant number：20K07703 2020.04 - 2023.03
科学研究費補助金 基盤研究(C)
Authorship：Principal investigator
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新規免疫チェックポイント分子Clec4A4によるがん免疫制御機構の解明
Grant number：17K15027 2017.04 - 2020.03
科学研究費補助金 若手研究(B)
Authorship：Principal investigator
Other research activities 【 display / non-display 】
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読売新聞「がん研究さらなる進歩を」
2024.01
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宮崎日日新聞「食物アレルギー抑制仕組み発見」
2018.02
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読売新聞「食物アレルギー抑制の細胞」
2018.02
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日本経済新聞「がん免疫薬で開発競争」
2017.08
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宮崎日日新聞「免疫反応の暴走抑制」
2016.05