Functional characterization of ultraviolet-expanded regulatory T cells in skin

• Project/Area Number: 19K07510
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Nagoya City University
• Principal Investigator: Shime Hiroaki 名古屋市立大学, 医薬学総合研究院(医学), 講師 (70372133)
• Co-Investigator(Kenkyū-buntansha): 山崎 小百合 名古屋市立大学, 医薬学総合研究院(医学), 教授 (70567255) ; 小田中 瑞夕 名古屋市立大学, 医薬学総合研究院(医学), 研究員 (00510281) ; 今井 優樹 名古屋市立大学, 医薬学総合研究院(医学), 講師 (30440936)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 制御性T細胞 / 創傷治癒 / 紫外線 / 皮膚 / 樹状細胞 / 炎症 / 免疫制御 / 免疫抑制

Outline of Research at the Start

皮膚に紫外線があたると、特定の樹状細胞サブセットの活性化により、免疫抑制細胞である制御性T細胞の割合が著しく増加する。本研究では、制御性T細胞の選択的な増殖がどのような機序で起こるのか、樹状細胞の活性化において起点となる免疫シグナルを中心に解明する。さらに、増加した制御性T細胞が皮膚の免疫疾患の治療や生理機能の恒常性を維持するのに役立つかどうか、新たな機能も含めて明らかにする。紫外線照射が人体にもたらす有益な作用を選択的に活用するための新たな方法論の確立を目指す。

Outline of Final Research Achievements

CD4-positive Fopx3-positive regulatory T cells (Tregs) are selectively accumulated in the ultraviolet (UV)-irradiated skin. Gene expression of UV-expanded skin Treg cells was compared with that of Treg cells or conventional T (Tconv) cells in lymph nodes and other tissues. We identified a specific pattern of gene expression in UVB-expanded skin Treg cells and found that they promote skin wound healing by producing proenkephalin (PENK) and amphiregulin (AREG) to promote proliferation and motility of keratinocytes.

Academic Significance and Societal Importance of the Research Achievements

紫外線が人体に及ぼす有害な作用は広く知られる一方、有益な作用があることはほとんど知られていない。炎症性皮膚疾患の治療に有効な紫外線の作用に、制御性T細胞が関与することが示唆されてきた。本研究では、それに加えて、紫外線照射によって増加した制御性T細胞が創傷治癒を促進する機能を持つことを明らかにした。得られた研究成果は、紫外線を用いて皮膚の自然治癒能を高める方法の開発につながることが期待できる。

Research Products

• [Journal Article] Foxp3+ CD4+ regulatory T cells control dendritic cells in inducing antigen-specific immunity to emerging SARS-CoV-2 antigens (2021)
  • Author(s): Uraki Ryuta、Imai Masaki、Ito Mutsumi、Shime Hiroaki、Odanaka Mizuyu、Okuda Moe、Kawaoka Yoshihiro、Yamazaki Sayuri
  • Journal Title: PLOS Pathogens Volume: 17 Issue: 12 Pages: e1010085-e1010085
  • DOI: 10.1371/journal.ppat.1010085
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reply to Slominski et al.: UVB irradiation induces proenkephalin+ regulatory T cells with a wound-healing function (2021)
  • Author(s): Shime Hiroaki、Odanaka Mizuyu、Tsuiji Makoto、Matoba Takuma、Imai Masaki、Yasumizu Yoshiaki、Uraki Ryuta、Minohara Kiyoshi、Watanabe Maiko、Bonito Anthony John、Fukuyama Hidehiro、Ohkura Naganari、Sakaguchi Shimon、Morita Akimichi、Yamazaki Sayuri
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 118 Issue: 3
  • DOI: 10.1073/pnas.2021919118
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Proenkephalin+regulatory T cells expanded by ultraviolet B exposure maintain skin homeostasis with a healing function (2020)
  • Author(s): Shime Hiroaki、Odanaka Mizuyu、Tsuiji Makoto、Matoba Takuma、Imai Masaki、Yasumizu Yoshiaki、Uraki Ryuta、Minohara Kiyoshi、Watanabe Maiko、Bonito Anthony John、Fukuyama Hidehiro、Ohkura Naganari、Sakaguchi Shimon、Morita Akimichi、Yamazaki Sayuri
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 117 Issue: 34 Pages: 20696-20705
  • DOI: 10.1073/pnas.2000372117
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hyperglycemia is associated with psoriatic inflammation in both humans and mice (2019)
  • Author(s): Ikumi K, Odanaka M, Shime H, Imai M, Osaga S, Taguchi O, Nishida E, Hemmi H, Kaisho T, Morita A, Yamazaki S
  • Journal Title: Journal of Investigative Dermatology Volume: 印刷中 Issue: 6 Pages: 1329-1338
  • DOI: 10.1016/j.jid.2019.01.029
  • Peer Reviewed / Open Access
• [Presentation] Proenkephalin+ regulatory T cells expanded by ultraviolet-B exposure maintain skin homeostasis with a healing function. (2021)
  • Author(s): Shime H, Odanaka M, Tsuiji M, Imai M, Yasumizu Y, Uraki R, Bonito A, Fukuyama H, Ohkura N, Sakaguchi S, Morita A, and Yamazaki S.
  • Organizer: 第50回日本免疫学会
• [Presentation] Transient depletion of Treg cells induces adaptive immunity to SARS-CoV-2 antigens. (2021)
  • Author(s): Uraki R, Imai M, Shime H, Kawaoka Y, Yamazaki S.
  • Organizer: 第50回日本免疫学会
• [Presentation] Skin regulatory T cells expanded by ultraviolet B exposure have a unique gene expression profile compared to other tissue Treg cells. (2021)
  • Author(s): Odanaka M, Shime H, Tsuiji M, Imai M, Yasumizu Y, Uraki R, Bonito A, Fukuyama H, Ohkura N, Sakaguchi S, Morita A, and Yamazaki S.
  • Organizer: 第50回日本免疫学会
• [Presentation] Skin regulatory T cells producing proenkephalin expand upon ultraviolet B exposure without ST2-IL33 axis and promote keratinocyte outgrowth. (2021)
  • Author(s): Yamazaki S, Shime H, Odanaka M, Tsuiji M, Matoba T, Imai M, Yasumizu Y, Uraki R, Minohara K, Watanabe M, Bonito A, Fukuyama H, Ohkura N, Sakaguchi S, Morita A.
  • Organizer: 第46回日本研究皮膚科学会
• [Presentation] 制御性T細胞を標的としたSARS-CoV-2に対する新規予防法の開発. (2021)
  • Author(s): 浦木隆太, 今井優樹, 伊藤睦美, 志馬寛明, 小田中瑞夕, 奥田萌, 河岡義裕, 山崎小百合
  • Organizer: 第68回日本ウイルス学会
• [Presentation] Skin regulatory T cells possessing a healing function are expanded by ultraviolet-B exposure. (2021)
  • Author(s): Yamazaki S, Shime H, Odanaka M, Tsuiji M, Matoba T, Imai M, Yasumizu Y, Uraki R, Minohara K, Watanabe M, Bonito A, Fukuyama H, Ohkura N, Sakaguchi S, Morita A.
  • Organizer: 第45回日本研究皮膚科学会
• [Presentation] Functional characterization of regulatory T (Treg) cells in UVB-irradiated skin (2019)
  • Author(s): Hiroaki Shime, Mizuyu Odanaka, Masaki Imai, Naganari Ohkura, Shimon Sakaguchi, Akimichi Morita, Sayuri Yamazaki
  • Organizer: 第48回 日本免疫学会学術集会
• [Presentation] Regulatory T cells with a distinctive feature expand through dermal dendritic cells in the ultraviolet B exposed skin (2019)
  • Author(s): Sayuri Yamazaki, Mizuyu Odanaka, Hiroaki Shime, Masaki Imai, Hiroaki Hemmi, Tsuneyasu Kaisho, Naganari Ohkura, Shimon Sakaguchi, Akimichi Morita
  • Organizer: 16th international workshop on Langerhans cells
  • Int'l Joint Research
• [Presentation] Dermal dendritic cells present neo-self antigens induced by ultraviolet B exposure to expand Foxp3+ regulatory T cells (2019)
  • Author(s): Sayuri Yamazaki, Mizuyu Odanaka, Hiroaki Shime, Masaki Imai, Hiroaki Hemmi, Tsuneyasu Kaisho, Naganari Ohkura, Shimon Sakaguchi, Akimichi Morita
  • Organizer: 77th annual meeting of Society for investigative dermatology
  • Int'l Joint Research
• [Presentation] Skin dendritic cells expressing a unique set of genes associated with immunological tolerance are specialized to expand thymus-derived Foxp3+ regulatory T cells upon ultraviolet B exposure (2019)
  • Author(s): Sayuri Yamazaki, Mizuyu Odanaka, Hiroaki Shime, Masaki Imai, Hiroaki Hemmi, Tsuneyasu Kaisho, Naganari Ohkura, Shimon Sakaguchi, Akimichi Morita
  • Organizer: Japan-Singapore Skin International Conference
  • Int'l Joint Research
• [Presentation] Characterization of Foxp3+ Regulatory T cells Expanded in Ultraviolet-B-irradiated Skin (2019)
  • Author(s): 兼子 ひとみ、小田中瑞夕、志馬寛明、山崎小百合
  • Organizer: 【新学術ネオ・セルフ】第3回若手の会