|
Affiliation |
Faculty of Medicine School of Medicine Department of Infectious Diseases, Immunology |
|
Title |
Associate Professor |
|
External Link |
|
|
Related SDGs |
|
UTO Tomofumi
|
|
|
Papers 【 display / non-display 】
-
Tahira Y, Shide K, Kameda T, Uchida T, Kamiunten A, Akizuki K, Kubuki Y, Karasawa M, Ikeda R, Matsumoto K, Bai J, Terashima M, Kato K, Uto T, Fukaya T, Mitoma S, Sato K, Uehira Y, Ueno H, Sashida G, Yamaguchi H, Shimoda K
Blood Neoplasia 2 ( 3 ) 100087 2025.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV
Interferon-α (IFN-α) exhibits antiviral and antiproliferative effects on normal and neoplastic cells. Intracellular signaling of IFN-α is mediated by tyrosine kinase 2 (TYK2) and janus kinase 1 (JAK1), followed by signal transducers and activators of transcription (STATs). TYK2 is redundant for the antiviral effect of IFN-α; however, the requirements for antiproliferative effects are unknown. We assessed the role of TYK2 in the effects of IFN-α in myeloproliferative neoplasm (MPN) model mice. Jak2V617F transgenic mice develop MPNs resembling human primary myelofibrosis, and ropeginterferon-α-2b ameliorated their features. However, these IFN-α effects were absent in Jak2V617F;Tyk2−/− mice. In mixed wild-type (WT)/Jak2V617F chimeric mice, IFN-α treatment induces Jak2V617F hematopoietic stem cells (HSCs) to enter the cell cycle and skew their differentiation into the megakaryocyte lineage, decreasing the number of Jak2V617F HSCs. The effects of IFN-α on Jak2V617F HSCs were not observed in mixed WT/Jak2V617F;Tyk2−/− mice, indicating that TYK2 is essential for the effects of IFN-α on both Jak2V617F progenitors and HSCs. The mechanism of IFN-α in Jak2V617F HSCs and progenitors differed: genes regulating the cell cycle were enriched in IFN-α–stimulated Jak2V617F HSCs, but not in Jak2V617F progenitors; genes regulating antiproliferation were enriched in IFN-α–stimulated Jak2V617F progenitors but not in Jak2V617F HSCs. The major IFN-α signaling molecule activated by JAKs is STAT1, which is essential for the antiviral effect. Most effects of IFN-α on Jak2V617F cells were preserved in Jak2V617F;Stat1−/− mice but to a moderate degree compared with Jak2V617F mice. Our study reveals essential roles of TYK2 for the preferential suppressive effect of IFN-α on Jak2V617F progenitors and HSCs.
-
Selectivity of bovine interleukin-2 mutein stimulation on bovine peripheral blood mononuclear cells Reviewed
MITOMA Shuya, UTO Tomofumi, FUKAYA Tomohiro, TOMINAGA Moe, SEKIGUCHI Satoshi, SATO Katsuaki, NORIMINE Junzo
Journal of Veterinary Medical Science 87 ( 7 ) 781 - 790 2025.7
Language：English Publishing type：Research paper (scientific journal) Publisher：JAPANESE SOCIETY OF VETERINARY SCIENCE
Delivery of engineered interleukin-2 (IL-2) variants (muteins) is thought to be a promising cancer therapy in humans and mice. Our previous study indicated that bovine IL-2 (boIL-2) has a great potential to elicit NK cell activity for which distribution of IL-2 receptors on the target cell surface influences signal transduction. We developed nine boIL-2 muteins and examined the influence of the muteins on bovine peripheral blood mononuclear cells <i>in vitro</i>. On bovine peripheral mononuclear cells, NK cells strongly expressed CD122, followed by CD8<sup>+</sup> T cells, while CD4<sup>+</sup> T cells and γδ T cells did not show significant CD122 expression. All boIL-2 muteins showed decreasing in binding to boIL-2 receptor α, CD25, while maintaining their ability to bind to boIL-2 receptor βγ, CD122/CD132, heterodimer. The mutein F44A and E63A suppressed CD4<sup>+</sup> T cell expansion but maintained the NK cell expansion. These results indicate that boIL-2 muteins can alter immunological outcomes and may be used for clinical intervention for a disease progression.
DOI： 10.1292/jvms.24-0470
-
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
-
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.
-
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.
Books 【 display / non-display 】
-
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.
-
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 】
-
樹状細胞のはたらき 8 樹状細胞を標的とした免疫チェックポイント阻害療法 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 37 26 - 31 2025.1
Authorship：Lead author Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (scientific journal)
-
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)
-
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)
-
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)
-
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)
Presentations 【 display / non-display 】
-
Induction of Cancer-Specific T Cell Responses by Dendritic Cells and Cancer Progression Control Based on the Engineering of an Immunogenic Tumor Microenvironment
Fukaya T., Uto T., Mitoma S., Sato K.
第29回日本がん免疫学会総会 2025.7.26
Event date： 2025.7.24 - 2025.7.26
Language：English Presentation type：Oral presentation (general)
-
Clec4A4 acts as immune checkpoint molecule expressed on conventional dendritic cells to suppress tumor immunity
Uto T., Fukaya T., Mitoma S., Sato K.
第29回日本がん免疫学会総会 2025.7.26
Event date： 2025.7.24 - 2025.7.26
Language：English Presentation type：Oral presentation (general)
-
新規樹状細胞発現免疫チェックポイントによるがん免疫応答制御 Invited
佐藤克明、宇都倫史
日本皮膚科学会第166回宮崎地方会－天野正宏教授退任記念－ 2025.3.8
Event date： 2025.3.8
Language：Japanese Presentation type：Oral presentation (invited, special)
-
Clec4A4/CLEC4A acts as a negative immune checkpoint regulator to suppress anti-tumor immunity
Uto T., Fukaya T., Mitoma S., Tominaga M., Sato K.
第53回日本免疫学会学術集会 2024.12.4
Event date： 2024.12.3 - 2024.12.5
Language：English Presentation type：Poster presentation
-
Clec4A4 Acts as a Negative Immune Checkpoint Regulator to Suppress Antitumor Immunity Invited International conference
Uto T., Sato K.
4th International Webinar on Oncology Research and Treatment 2024.11.29
Event date： 2024.11.28 - 2024.11.29
Language：English Presentation type：Oral presentation (invited, special)
Awards 【 display / non-display 】
-
第一回新日本先進医療研究財団優秀研究者賞
2025.3 公益財団法人 新日本先進医療研究財団 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
宇都 倫史
Award type：Award from publisher, newspaper, foundation, etc.
Grant-in-Aid for Scientific Research 【 display / non-display 】
-
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：23K27464 2023.04 - 2026.03
独立行政法人日本学術振興会 科学研究費基金 基盤研究(B)
Authorship：Principal investigator
-
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
-
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 】
-
読売新聞「がん研究さらなる進歩を」
2024.01
-
宮崎日日新聞「食物アレルギー抑制仕組み発見」
2018.02
-
読売新聞「食物アレルギー抑制の細胞」
2018.02
-
日本経済新聞「がん免疫薬で開発競争」
2017.08
-
宮崎日日新聞「免疫反応の暴走抑制」
2016.05