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Affiliation |
Faculty of Medicine School of Medicine Department of Infectious Diseases, Immunology |
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Assistant Professor |
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External Link |
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Fukaya Tomohiro
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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
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
Authorship：Lead author 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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Yano K., Choijookhuu N., Ikenoue M., Fidya , Fukaya T., Sato K., Lee D., Taniguchi N., Chosa E., Nanashima A., Hishikawa Y.
Scientific Reports 12 ( 1 ) 11962 2022.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports
Liver regeneration is an extraordinarily complex process involving a variety of factors; however, the role of chromatin protein in hepatocyte proliferation is largely unknown. In this study, we investigated the functional role of high-mobility group box 2 (HMGB2), a chromatin protein in liver regeneration using wild-type and HMGB2-knockout (KO) mice. Liver tissues were sampled after 70% partial hepatectomy (PHx), and analyzed by immunohistochemistry, western blotting and flow cytometry using various markers of cell proliferation. In WT mice, hepatocyte proliferation was strongly correlated with the spatiotemporal expression of HMGB2; however, cell proliferation was significantly delayed in hepatocytes of HMGB2-KO mice. Quantitative PCR demonstrated that cyclin D1 and cyclin B1 mRNAs were significantly decreased in HMGB2-KO mice livers. Interestingly, hepatocyte size was significantly larger in HMGB2-KO mice at 36–72 h after PHx, and these results suggest that hepatocyte hypertrophy appeared in parallel with delayed cell proliferation. In vitro experiments demonstrated that cell proliferation was significantly decreased in HMGB2-KO cells. A significant delay in cell proliferation was also found in HMGB2-siRNA transfected cells. In summary, spatiotemporal expression of HMGB2 is important for regulation of hepatocyte proliferation and cell size during liver regeneration.
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Congenital Deficiency of Conventional Dendritic Cells Promotes the Development of Atopic Dermatitis-Like Inflammation Reviewed International coauthorship
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
Authorship：Lead author 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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Miyanaga N., Takagi H., Uto T., Fukaya T., Nasu J., Fukui T., Nishikawa Y., Sparwasser T., Choijookhuu N., Hishikawa Y., Nakamura T., Tono T., Sato K.
Communications Biology 3 ( 1 ) 742 2020.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Communications Biology
While sublingual immunotherapy (SLIT) is known as an allergen-specific treatment for type-1 allergies, how it controls allergic pathogenesis remains unclear. Here, we show the prerequisite role of conventional dendritic cells in submandibular lymph nodes (ManLNs) in the effectiveness of SLIT for the treatment of allergic disorders in mice. Deficiency of conventional dendritic cells or CD4+Foxp3+ regulatory T (Treg) cells abrogates the protective effect of SLIT against allergic disorders. Furthermore, sublingual antigenic application primarily induces antigen-specific CD4+Foxp3+ Treg cells in draining ManLNs, in which it is severely impaired in the absence of cDCs. In ManLNs, migratory CD11b+ cDCs are superior to other conventional dendritic cell subsets for the generation of antigen-specific CD4+Foxp3+ Treg cells, which is reflected by their dominancy in the tolerogenic features to favor this program. Thus, ManLNs are privileged sites in triggering mucosal tolerance mediating protect effect of SLIT on allergic disorders that requires a tolerogenesis of migratory CD11b+ conventional dendritic cells.
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 , Regulatory dendritic cells）
Springer Publishing 2017.9
Language：English Book type：Scholarly book
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Methods in Molecular Biology
Fukaya, T., Takagi, H., Uto, T, Arimura, K., and Sato, K.（ Role： Joint author , Analysis of DC functions using CD205-DTR knock-in mice）
Springer Publishing 2016.5
Language：English Book type：Scholarly book
MISC 【 display / non-display 】
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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
深谷知宏•宇都倫史•三苫修也•佐藤克明
Veterinary Immunology for Practitioners ( 34 ) 15 - 21 2024.4
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
深谷知宏•宇都倫史•三苫修也•佐藤克明
Veterinary Immunology for Practitioners ( 33 ) 15 - 19 2024.1
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③樹状細胞による制御性T細胞の制御 Invited
深谷知宏•宇都倫史•三苫修也•佐藤克明
Veterinary Immunology for Practitioners ( 32 ) 2 - 7 2023.10
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②pDCsによる免疫応答制御 Invited
宇都倫史•深谷知宏•三苫修也•佐藤克明
Veterinary Immunology for Practitioners ( 31 ) 26 - 31 2023.7
Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (scientific journal)
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樹状細胞のはたらき①樹状細胞亜集団と免疫応答制御 Invited
宇都倫史•深谷知宏•三苫修也•佐藤克明
Veterinary Immunology for Practitioners ( 30 ) 32 - 38 2023.4
Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (scientific journal)
Presentations 【 display / non-display 】
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Gut dysbiosis abrogates the establishment of oral tolerance mediated through dysfunction of mucosal dendritic cells
深谷知宏、宇都倫史、三笘修也、冨永萌、佐藤克明
第52回日本免疫学会総会 2024.1.17
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
三笘修也、宇都倫史、深谷知宏、冨永萌、佐藤克明
第52回日本免疫学会総会 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
冨永萌、宇都倫史、深谷知宏、三笘修也、佐藤克明
第52回日本免疫学会総会 2024.1.18
Event date： 2024.1.17 - 2024.1.19
Language：English Presentation type：Poster presentation
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Clec4A4 serves as a negative immune checkpoint regulator expressed on conventional dendritic cells to impair antitumor immunity
宇都倫史、深谷知宏、三笘修也、冨永萌、佐藤克明
第52回日本免疫学会総会 2024.1.18
Event date： 2024.1.17 - 2024.1.19
Language：English Presentation type：Poster presentation
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DCIR2 is an immune regulatory molecule expressed on conventional dendritic cells to suppress tumor immunity International conference
Uto T, Tominaga M, Fukaya T, Mitoma S, Sato K.
JSICR/MMCB 2023 Joint Symposium (Ito International Research Center, University of Tokyo) 2023.5.25
Event date： 2023.5.25 - 2023.5.26
Language：English Presentation type：Poster presentation
Venue：Ito International Research Center, University of Tokyo
Awards 【 display / non-display 】
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第51回日本免疫学会学術集会 ベストポスター賞
2022.12 日本免疫学会 Gut dysbiosis abrogates the establishment of oral tolerance through the dysregulation of the crosstalk between CD103 + conventional dendritic cells and innate lymphoid cells in mesenteric lymph nodes
深谷知宏
Award type：Award from Japanese society, conference, symposium, etc.
Grant-in-Aid for Scientific Research 【 display / non-display 】
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形質細胞様樹状細胞の機能制御分子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：23K06768 2023.04 - 2026.03
独立行政法人日本学術振興会 科学研究費補助金 基盤研究(C)
Authorship：Principal investigator
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IL-22結合タンパクによる皮膚炎症慢性化に対する制御機構の解明
2017.04 - 2020.03
科学研究費補助金 若手研究(B)
Authorship：Principal investigator
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CD4陽性通常型樹状細胞による自己免疫疾患の制御機構の解明
2014.04 - 2017.03
科学研究費補助金 若手研究(B)
Authorship：Principal investigator
CD4陽性通常型樹状細胞による自己免疫疾患の制御機構の解明