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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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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)
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Nishikawa Y., Fukaya T., Fukui T., Uto T., Takagi H., Nasu J., Miyanaga N., Riethmacher D., Choijookhuu N., Hishikawa Y., Amano M., Sato K.
Frontiers in Immunology 12 712676 2021.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers in Immunology
Atopic dermatitis (AD) is a common pruritic inflammatory skin disease characterized by impaired epidermal barrier function and dysregulation of Thelper-2 (TH2)-biased immune responses. While the lineage of conventional dendritic cells (cDCs) are implicated to play decisive roles in T-cell immune responses, their requirement for the development of AD remains elusive. Here, we describe the impact of the constitutive loss of cDCs on the progression of AD-like inflammation by using binary transgenic (Tg) mice that constitutively lacked CD11chi cDCs. Unexpectedly, the congenital deficiency of cDCs not only exacerbates the pathogenesis of AD-like inflammation but also elicits immune abnormalities with the increased composition and function of granulocytes and group 2 innate lymphoid cells (ILC2) as well as B cells possibly mediated through the breakdown of the Fms-related tyrosine kinase 3 ligand (Flt3L)-mediated homeostatic feedback loop. Furthermore, the constitutive loss of cDCs accelerates skin colonization of Staphylococcus aureus (S. aureus), that associated with disease flare. Thus, cDCs maintains immune homeostasis to prevent the occurrence of immune abnormalities to maintain the functional skin barrier for mitigating AD flare.
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Characterization of bovine interleukin-2 stably expressed in HEK-293 cells. Reviewed
Mitoma S, El-Khaiat HM, Uto T, Sato K, Sekiguchi S, Norimine J
The Journal of veterinary medical science 83 ( 1 ) 134 - 141 2021.1
Language：English Publishing type：Research paper (scientific journal) Publisher：公益社団法人 日本獣医学会
Interleukin 2 (IL-2) is a pleotropic cytokine and well-known as a T cell growth factor in immunology. It is now known to exert both immunostimulatory and immunosuppressive effects, optimizing immunological microenvironments for effector and regulatory T cell responses. The immunomodulatory role of IL-2 is critical for deciding whether or not T cell responses against specific antigens result in protection. We have established a mammalian cell line (HEK-293) stably expressing bovine IL-2 (boIL-2) (designated as HEK-293/boIL-2), using the piggyBac transposon system. The concentration of recombinant bovine IL-2 (rboIL-2) in the culture supernatant of HEK-293/boIL-2 reached 100 ng/ml on day 7 and showed similar proliferative activity to recombinant human IL-2 (rhuIL-2) for bovine peripheral mononuclear blood cells. Although rhuIL-2 has been often used to activate bovine T cells, our results indicate that characteristics of the T cell activation through rboIL-2 and huIL-2 appear slightly but significantly different. Interestingly, the rboIL-2/anti-boIL-2 monoclonal antibody (C5) (rboIL-2/C5) complex strongly induced proliferation of bovine NKp46<sup>+</sup>cells, natural killer (NK) cells, <i>in vitro</i>. This indicates that the rboIL-2/C5 complex could function as an IL-2 agonist specifically to increase the NK cell population, which in turn could enhance the activity of NK cells leading to protective immunity.
DOI： 10.1292/jvms.20-0423
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 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：Rapid communication, short report, research note, 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 2 - 7 2023.10
Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (scientific journal)
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樹状細胞のはたらき２ 樹状細胞のはたらき pDCsによる免疫応答制御 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 31 26 - 31 2023.7
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１ 樹状細胞亜集団と免疫応答制御 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 30 32 - 38 2023.4
Authorship：Lead author Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (scientific journal)
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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
宇都倫史, 深谷知宏, 三苫修也, 佐藤克明
腫瘍内科 31 ( 3 ) 300 - 306 2023.3
Authorship：Lead author Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (scientific journal)
Presentations 【 display / non-display 】
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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
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Crucial role of conventional dendritic cells in the generation of anti-tumor T-cell responses and immunogenic tumor microenvironment to suppress tumor development International conference
Tominaga M., Uto T., Fukaya T., Mitoma S., 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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Crucial role of dendritic cells in the suppression of tumor development
Tominaga M., Uto T., Fukaya T., Mitoma, S., Yamashita Y., Sato K.
第61回日本癌治療学会学術集会 2023.10.21
Event date： 2023.10.19 - 2023.10.21
Language：English Presentation type：Oral presentation (general)
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