論文 - 深谷 知宏
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Clec4A4 Acts As A Negative Immune Checkpoint Regulator to Suppress Antitumor Immunity. 査読あり
Uto T, Fukaya T, Mitoma S, Nishikawa Y, Tominaga M, Choijookhuu N, Hishikawa Y, Sato K
Cancer immunology research 11 ( 9 ) 1266 - 1279 2023年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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年5月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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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TYK2 is essential for the therapeutic effect of IFN-α in Jak2V617F-induced murine myeloproliferative neoplasms 査読あり
Yuki Tahira , Kotaro Shide , Takuro Kameda , Taisuke Uchida , Ayako Kamiunten , Keiichi Akizuki , Yoko Kubuki , Masayoshi Karasawa , Ryoma Ikeda , Kengo Matsumoto , Jie Bai , Minoru Terashima , Koji Kato , Tomofumi Uto , Tomohiro Fukaya , Shuya Mitoma , Katsuaki Sato , Yudai Uehira , Hiroaki Ueno , Goro Sashida , Hideki Yamaguchi , Kazuya Shimoda
Blood Neoplasia 2 ( 3 ) 100087 2025年8月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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Selectivity of bovine interleukin-2 mutein stimulation on bovine peripheral blood mononuclear cells. 査読あり
Mitoma S, Uto T, Fukaya T, Tominaga M, Sekiguchi S, Sato K, Norimine J
The Journal of veterinary medical science advpub ( 0 ) 2025年5月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：公益社団法人 日本獣医学会
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
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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 査読あり 国際共著
Tominaga M., Uto T., Fukaya T., Mitoma S., Riethmacher D., Umekita K., Yamashita Y., Sato K.
Frontiers in Immunology 15 1200461 2024年8月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Frontiers in Immunology
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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年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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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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年7月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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.
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Pivotal role of carbohydrate recognition domain in self-interaction of CLEC4A to elicit the ITIM-mediated inhibitory function in murine conventional dendritic cells in vitro. 査読あり
Nasu J, Uto T, Fukaya T, Takagi H, Fukui T, Miyanaga N, Nishikawa Y, Yamasaki S, Yamashita Y, Sato K
International immunology 32 ( 10 ) 673 - 682 2020年9月
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Pivotal role of CD103 in the development of psoriasiform dermatitis 査読あり
Fukui T., Fukaya T., Uto T., Takagi H., Nasu J., Miyanaga N., Nishikawa Y., Koseki H., Choijookhuu N., Hishikawa Y., Yamashita Y., Sato K.
Scientific Reports 10 ( 1 ) 8371 2020年5月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Scientific Reports
© 2020, The Author(s). The integrin αE known as CD103 binds integrin β7 to form the complete heterodimeric integrin molecule αEβ7. CD103 is mainly expressed by lymphocytes within epithelial tissues of intestine, lung, and skin as well as subsets of mucosal and dermal conventional dendritic cells (cDCs). CD103 has been originally implicated in the attachment of lymphocytes to epithelium in the gut and skin through the interaction with E-cadherin expressed on intestinal epithelial cells, keratinocytes, and Langerhans cells (LCs). However, an impact of CD103 on the cutaneous immune responses and the development of inflammatory skin diseases remains elusive. Here, we report that CD103 regulates the development of psoriasiform dermatitis through the control of the function of cDCs. Deficiency in CD103 exacerbates psoriasiform dermatitis, accompanied by excessive epidermal hyperplasia and infiltration of inflammatory leukocytes. Furthermore, deficiency in CD103 not only accelerates the production of proinflammatory cytokines in psoriatic lesions but also promotes the generation of lymphocytes producing interleukin (IL)-17 in the skin-draining peripheral lymph nodes (PLNs). Under the deficiency in CD103, cDCs localized in PLNs enhance cytokine production following activation. Thus, our findings reveal a pivotal role for CD103 in the control of the function of cDCs to regulate cutaneous inflammation in psoriasiform dermatitis.
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ER-resident sensor PERK is essential for mitochondrial thermogenesis in brown adipose tissue 査読あり
Kato, H. Okabe, K., Miyake, M., Hattori, K., Fukaya, T., Tanimoto, K., Beini, S., Mizuguchi, M., Torii, S., Arakawa, S., Ono, M., Saito, Y., Suguyama, T., Funatsu, T., Sato, K., Shimizu, S., Oyadomari, S., Ichijo, H., Kadowaki, H., and Nishitoh, H.
Life Science Alliance 3 e201900576 2020年2月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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Fukaya T., Fukui T., Uto T., Takagi H., Nasu J., Miyanaga N., Arimura K., Nakamura T., Koseki H., Choijookhuu N., Hishikawa Y., Sato K.
Frontiers in Immunology 9 ( JUN ) 1418 2018年6月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Frontiers in Immunology
© 2018 Fukaya, Fukui, Uto, Takagi, Nasu, Miyanaga, Arimura, Nakamura, Koseki, Choijookhuu, Hishikawa and Sato. Disruption of skin homeostasis can lead to inflammatory cutaneous diseases resulting from the dysregulated interplay between epithelial keratinocytes and immune cells. Interleukin (IL)-22 signaling through membrane-bound IL-22 receptor 1 (IL-22R1) is crucial to maintain cutaneous epithelial integrity, and its malfunction mediates deleterious skin inflammation. While IL-22 binding protein (IL-22BP) binds IL-22 to suppress IL-22 signaling, how IL-22BP controls epithelial functionality to prevent skin inflammation remains unclear. Here, we describe the pivotal role of IL-22BP in mediating epithelial autoregulation of IL-22 signaling for the control of cutaneous pathogenesis. Unlike prominent expression of IL-22BP in dendritic cells in lymphoid tissues, epidermal keratinocytes predominantly expressed IL-22BP in the skin in the steady state, whereas its expression decreased during the development of psoriatic inflammation. Deficiency in IL-22BP aggravates psoriasiform dermatitis, accompanied by abnormal hyperproliferation of keratinocytes and excessive cutaneous inflammation as well as enhanced dermal infiltration of granulocytes and γδT cells. Furthermore, IL-22BP abrogates the functional alternations of keratinocytes upon stimulation with IL-22. On the other hand, treatment with IL-22BP alleviates the severity of cutaneous pathology and inflammation in psoriatic mice. Thus, the fine-tuning of IL-22 signaling through autocrine IL-22BP production in keratinocytes is instrumental in the maintenance of skin homeostasis.
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Critical role of plasmacytoid dendritic cells in induction of oral tolerance 査読あり
Uto T., Takagi H., Fukaya T., Nasu J., Fukui T., Miyanaga N., Arimura K., Nakamura T., Choijookhuu N., Hishikawa Y., Sato K.
Journal of Allergy and Clinical Immunology 141 ( 6 ) 2156 - 2167.e9 2018年6月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Allergy and Clinical Immunology
© 2018 American Academy of Allergy, Asthma & Immunology Background: Exposure to dietary constituents through the mucosal surface of the gastrointestinal tract generates oral tolerance that prevents deleterious T cell–mediated immunity. Although oral tolerance is an active process that involves emergence of CD4+ forkhead box p3 (Foxp3)+ regulatory T (Treg) cells in gut-associated lymphoid tissues (GALTs) for suppression of effector T (Teff) cells, how antigen-presenting cells initiate this process remains unclear. Objective: We sought to determine the role of plasmacytoid dendritic cells (pDCs), which are known as unconventional antigen-presenting cells, in establishment of oral tolerance. Methods: GALT-associated pDCs in wild-type mice were examined for their ability to induce differentiation of CD4+ Teff cells and CD4+Foxp3+ Treg cells in vitro. Wild-type and pDC-ablated mice were fed oral antigen to compare their intestinal generation of CD4+Foxp3+ Treg cells and induction of oral tolerance to protect against Teff cell–mediated allergic inflammation. Results: GALT-associated pDCs preferentially generate CD4+Foxp3+ Treg cells rather than CD4+ Teff cells, and such generation requires an autocrine loop of TGF-β for its robust production. A deficiency of pDCs abrogates antigen-specific de novo generation of CD4+Foxp3+ Treg cells occurring in GALT after antigenic feeding. Furthermore, the absence of pDCs impairs development of oral tolerance, which ameliorates the progression of delayed-type hypersensitivity and systemic anaphylaxis, as well as allergic asthma, accompanied by an enhanced antigen-specific CD4+ Teff cell response and antibody production. Conclusion: pDCs are required for establishing oral tolerance to prevent undesirable allergic responses, and they might serve a key role in maintaining gastrointestinal immune homeostasis.
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Arimura K., Takagi H., Uto T., Fukaya T., Nakamura T., Choijookhuu N., Hishikawa Y., Yamashita Y., Sato K.
Mucosal Immunology 10 ( 4 ) 957 - 970 2017年7月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Mucosal Immunology
© 2017 Society for Mucosal Immunology. Disruption of intestinal homeostasis can lead to inflammatory bowel diseases endowed susceptibility genes and environmental factors affecting intestinal accumulation and activation of colitogenic phagocytes. Plasmacytoid dendritic cells (pDCs) are immune cells that had been proposed to control innate and adaptive immunity through the massive secretion of type I interferon (IFN-I). However, the contribution of pDCs to the progression of intestinal inflammation remains unclear. Here we show a critical role of pDCs in the initiation of acute colonic inflammation using T-cell-independent acute colitis model with a selective ablation of pDCs. Although pDCs accumulated in the inflamed colon upon mucosal injury, deficiency of pDCs attenuated the development of acute colitis independent of IFN-I signaling, accompanied by the diminished colonic production of proinflammatory cytokines. Furthermore, deficiency of pDCs impaired the mobilization of colitogenic phagocytes into the inflamed colon possibly mediated by the abrogated mucosal production of C-C chemokine receptor 2 ligand. Thus, our findings highlight a critical role of pDCs in the induction of the colonic inflammation that regulates the colonic accumulation of inflammatory phagocytes leading to the initiation and exacerbation of acute colitis, and they may serve a key role in controlling gut mucosal immune homeostasis.
DOI： 10.1038/mi.2016.96
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Selective depletion of basophils ameliorates immunoglobulin E-mediated anaphylaxis 査読あり
Nakamura, T., Fukaya, T., Uto, T., Takagi, H., Arimura, K.,Tono, T., and Sato, K
Biochemistry and Biophysics Reports 29 - 35 2017年3月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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Plasmacytoid dendritic cells orchestrate TLR7-mediated innate and adaptive immunity for the initiation of utoimmune inflammation 査読あり
Takagi, H., Arimura, K., Uto, T., Fukaya, T., Nakamura, T., Choijookhuu, N., Hishikawa, Y., and Sato, K
Scientific Reports 2016年4月
記述言語：英語 掲載種別：研究論文（学術雑誌）
DOI： 10.1038/srep24477
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Clec4A4 is a regulatory receptor for dendritic cells that impairs inflammation and T-cell immunity 査読あり
Uto, T.*, Fukaya, T.*, Takagi, H., Arimura, K., Nakamura, T., Kojima, N., Malissen, B., and Sato, K *Contributed equally to this work
Nature Communications 2016年4月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌）
DOI： 10.1038/ncomms11273
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Loss of Sprouty4 in T cells ameliorates experimental autoimmune encephalomyelitis in mice by negatively regulating IL-1β receptor expression 査読あり
Tomohiro fukaya,Kazue someya,Sana hibino,Okada humitsugu,Koji taniguchi,Akihiko yoshimura
Biochemical and biophysical research communications 447 ( 3 ) 471 - 478 2014年5月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌）
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Aryl hydrocarbon receptor plays protective roles in ConA-induced hepatic injury by both suppressing IFN-γ expression and inducing IL-22(共著) 査読あり
Hiromi Abe, Akihiro Kimura, Sanae Tsuruta, Tomohiro Fukaya, Ryota Sakaguchi, Rimpei Morita, Takashi Sekiya, Takashi Shichita, Kazuaki Chayama, Yoshiaki Fujii-Kuriyama, and Akihiko Yoshimura
international immunology 2014年3月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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Smad2/3 and IRF4 play a cooperative role in IL-9-producing T cell induction. 査読あり
Tamiya T, Ichiyama K, Kotani H, Fukaya T, Sekiya T, Shichita T, Honma K, Yui K, Matsuyama T, Nakao T, Fukuyama S, Inoue H, Nomura M, Yoshimura A
Journal of immunology (Baltimore, Md. : 1950) 191 ( 5 ) 2360 - 71 2013年9月