T cell surveillance mechanisms in peripheral tissues

• Project/Area Number: 19K08748
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Kyoto University
• Principal Investigator: EGAWA GYOHEI 京都大学, 医学研究科, 講師 (50511812)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: T cell / homeostatic expansion / skin / homeostasis / T細胞 / 皮膚免疫 / 骨髄移植 / 抗原提示 / 樹状細胞 / ケモカイン / 生体イメージング

Outline of Research at the Start

エフェクターＴ細胞は、獲得免疫において中心的な役割を担う細胞群である。本細胞群は、血液中を循環し炎症部位へ集積するのみならず、炎症の生じていない末梢組織にも自ら浸潤し、非自己抗原の検索（homeostaticサーベイランス）を行うと考えられている。しかしその実態およびメカニズムについては不明の点が多い。本研究は、この「静の免疫応答」にスポットをあて、炎症のない状態の皮膚へのＴ細胞浸潤メカニズムの解明をめざす異色の研究である。Homeostaticサーベイランスが過剰に生じるマウスモデルを独自に考案し、遺伝子改変マウス、生体イメージングといったツールを駆使して本目的の達成を目指す。

Outline of Final Research Achievements

In this study, we aimed to elucidate how T cells infiltrate into non-inflamed skin using "homeostatic expansion" model. In this model, T cells proliferated markedly by 7 days after transfer, and many T cells migrated to the skin without inflammation. Almost all proliferated T cells were memory-phenotype (CD44+) and showed a tendency to differentiate into Th1 and Th17. In vivo imaging showed that CD8+ T cells infiltrated into the epidermis, especially around the hair follicles, and remained in the skin for more than 60 days. Dermatitis developed spontaneously when regulatory T cells are excluded during T cell transfer.

Academic Significance and Societal Importance of the Research Achievements

抗原非特異的にT細胞が増殖するHomeostatic expansionという現象は、生理的には新生児期、骨髄移植後、免疫抑制状態（AIDS患者や免疫抑制剤使用患者）からの回復時などで見られる。これらの状態では、新生児中毒性紅斑、脂漏性皮膚炎、好酸球性膿疱性毛包炎、免疫再構築症候群（IRIS）などの病態が生じることが知られる。本研究の成果からこれらの病態では炎症のない皮膚へのT細胞浸潤が増加し、host-parasite relationshipの変化が生じることが示唆された。この現象のメカニズム解明が進めば、これらの病態を制御する新たな治療標的などへとつながる可能性がある。

Research Products

• [Journal Article] Mast cells in type 2 skin inflammation: Maintenance and function (2023)
  • Author(s): Keith Yuki Honda、Egawa Gyohei、Honda Tetsuya、Kabashima Kenji
  • Journal Title: European Journal of Immunology Volume: In press Issue: 8 Pages: 2250359-2250359
  • DOI: 10.1002/eji.202250359
  • Peer Reviewed
• [Journal Article] A case of Kimura disease with atopic dermatitis successfully treated with baricitinib (2023)
  • Author(s): Ueda Marina、Kogame Toshiaki、Egawa Gyohei、Kambe Naotomo、Kabashima Kenji
  • Journal Title: The Journal of Dermatology Volume: In press Issue: 6 Pages: 196-197
  • DOI: 10.1111/1346-8138.16724
  • Peer Reviewed
• [Journal Article] Waves of layered immunity over innate lymphoid cells (2022)
  • Author(s): Kogame Toshiaki、Egawa Gyohei、Nomura Takashi、Kabashima Kenji
  • Journal Title: Frontiers in Immunology Volume: 13
  • DOI: 10.3389/fimmu.2022.957711
  • Peer Reviewed
• [Journal Article] A Phenotypic Analysis of Involucrin?Membrane-Bound Ovalbumin Mice after Adoptive Transfer of Ovalbumin-Specific CD8+ T Cells (2022)
  • Author(s): Nakagawa Yujin、Egawa Gyohei、Miyake Toshiya、Nakajima Saeko、Otsuka Atsushi、Nomura Takashi、Kitoh Akihiko、Dainichi Teruki、Sakabe Jun-ichi、Shibaki Akihiko、Tokura Yoshiki、Honda Tetsuya、Kabashima Kenji
  • Journal Title: JID Innovations Volume: 2 Issue: 5 Pages: 100127-100127
  • DOI: 10.1016/j.xjidi.2022.100127
  • Peer Reviewed
• [Journal Article] Circadian rhythm affects the magnitude of contact hypersensitivity response in mice (2022)
  • Author(s): Miyake Toshiya、Egawa Gyohei、Chow Zachary、Asahina Ryota、Otsuka Masayuki、Nakajima Saeko、Nomura Takashi、Shibuya Rintaro、Ishida Yoshihiro、Nakamizo Satoshi、Murata Teruasa、Kitoh Akihiko、Kabashima Kenji
  • Journal Title: Allergy Volume: 77 Issue: 9 Pages: 2748-2759
  • DOI: 10.1111/all.15314
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CCL2?CCR2 Signaling in the Skin Drives Surfactant-Induced Irritant Contact Dermatitis through IL-1β?Mediated Neutrophil Accumulation (2022)
  • Author(s): Shibuya Rintaro、Ishida Yoshihiro、Hanakawa Sho、Kataoka Tatsuki R.、Takeuchi Yasuhide、Murata Teruasa、Akagi Arisa、Chow Zachary、Kogame Toshiaki、Nakamizo Satoshi、Nakajima Saeko、Egawa Gyohei、Nomura Takashi、Kambe Naotomo、Kitoh Akihiko、Kabashima Kenji
  • Journal Title: Journal of Investigative Dermatology Volume: 142 Issue: 3 Pages: 571-582
  • DOI: 10.1016/j.jid.2021.07.182
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolonged high-intensity exercise induces fluctuating immune responses to herpes simplex virus infection via glucocorticoids (2021)
  • Author(s): Adachi, A., Honda, T., Dainichi, T., Egawa, G., Yamamoto, Y., Nomura, T., Nakajima, S., Otsuka, A., Maekawa, M., Mano, N., Koyanagi, N., Kawaguchi, Y., Ohteki, T., Nagasawa, T., Ikuta, K., Kitoh, A., and Kabashima, K.
  • Journal Title: J. Allergy Clin. Immunol. Volume: 148 Issue: 6 Pages: 1575-1588.e7
  • DOI: 10.1016/j.jaci.2021.04.028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A new player in the dermis (2021)
  • Author(s): Egawa Gyohei、Kabashima Kenji
  • Journal Title: eLife Volume: 10
  • DOI: 10.7554/elife.68979
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Putative Immunological Functions of Inducible Skin-Associated Lymphoid Tissue in the Context of Mucosa-Associated Lymphoid Tissue (2021)
  • Author(s): Kogame Toshiaki、Kabashima Kenji、Egawa Gyohei
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 733484-733484
  • DOI: 10.3389/fimmu.2021.733484
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cutaneous Liver X Receptor Activation Prevents the Formation of Imiquimod-Induced Psoriatic Dermatitis. (2021)
  • Author(s): Otsuka M., Egawa G., Dainichi T., Okuno T., Ishida Y., Chow Z., Asahina R., Miyake T., Nomura T., Kitoh A., Yokomizo T., Kabashima K.
  • Journal Title: Journal of Investigative Dermatology Volume: 142(4) Issue: 4 Pages: 1233-1237.e1
  • DOI: 10.1016/j.jid.2021.08.432
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PD-L1 on mast cells suppresses effector CD8+ T-cell activation in the skin in murine contact hypersensitivity (2021)
  • Author(s): Hirano Tomoko、Honda Tetsuya、Kanameishi Shuto、Honda Yuki、Egawa Gyohei、Kitoh Akihiko、Nakajima Saeko、Otsuka Atsushi、Nomura Takashi、Dainichi Teruki、Yaguchi Tomonori、Inozume Takashi、Kataoka Tatsuki R.、Tamada Koji、Kabashima Kenji
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: in press Issue: 2 Pages: 00178-00178
  • DOI: 10.1016/j.jaci.2020.12.654
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intravital Imaging of Vascular Permeability by Two-Photon Microscopy. (2021)
  • Author(s): Egawa G, Ono S, Kabashima K.
  • Journal Title: Methods Mol Biol. Volume: 2223 Pages: 151-157
  • DOI: 10.1007/978-1-0716-1001-5_11
  • ISBN: 9781071610008, 9781071610015
  • Peer Reviewed
• [Journal Article] Bacterial antigen is directly delivered to the draining lymph nodes and activates CD8+ T cells during Staphylococcus aureus skin infection. (2020)
  • Author(s): Egawa G, Roediger B, Tay SS, L Cavanagh L, V Guy T, Fazekas de B, Brzoska AJ, Firth N, Weninger W.
  • Journal Title: Immunol Cell Biol. 2021 Mar;99(3):299-308 Volume: 99 Issue: 3 Pages: 299-308
  • DOI: 10.1111/imcb.12410
  • Peer Reviewed
• [Journal Article] THE MECHANISM OF ITCH (2020)
  • Author(s): 江川形平
  • Journal Title: Japanese Journal of Allergology Volume: 69 Issue: 4 Pages: 256-259
  • DOI: 10.15036/arerugi.69.256
  • NAID: 130007853937
  • ISSN: 0021-4884, 1347-7935
• [Journal Article] Role of Lymphoid Structure in Skin Immunity. (2020)
  • Author(s): Egawa G, Kabashima K.
  • Journal Title: Curr Top Microbiol Immunol. Volume: 426 Pages: 65-82
  • DOI: 10.1007/82_2020_206
  • ISBN: 9783030517465, 9783030517472
• [Journal Article] IN VIVO IMAGING OF CUTANEOUS INFLAMMATION: NOVEL INSIGHTS INTO CUTANEOUS IMMUNE RESPONSES REVEALED BY INTRAVITAL IMAGING TECHNIQUES (2020)
  • Author(s): Honda T, Egawa G, Kabashima K.
  • Journal Title: Japanese Journal of Allergology Volume: 69 Issue: 2 Pages: 93-98
  • DOI: 10.15036/arerugi.69.93
  • NAID: 130007809360
  • ISSN: 0021-4884, 1347-7935
  • Peer Reviewed
• [Journal Article] Janus kinase inhibitor delgocitinib suppresses pruritus and nerve elongation in an atopic dermatitis murine model. (2020)
  • Author(s): Yamamoto Y, Otsuka A, Nakashima C, Ishida Y, Honda T, Egawa G, Amano W, Usui K, Hamada Y, Wada M, Tanimoto A, Konishi N, Hayashi M, Matsushita M, Kabashima K.
  • Journal Title: J Dermatol Sci Volume: － Issue: 2 Pages: 0-0
  • DOI: 10.1016/j.jdermsci.2019.12.008
  • Peer Reviewed
• [Journal Article] Abl family tyrosine kinases govern IgG extravasation in the skin in a murine pemphigus model (2019)
  • Author(s): Ono S, Egawa G, Nomura T, Kitoh A, Dainichi T, Otsuka A, Nakajima S, Amagai M, Matsumoto F, Yamamoto M, Kubota Y, Takai T, Honda T, Kabashima K.
  • Journal Title: Nat Commun Volume: 10(1) Issue: 1 Pages: 4432-4432
  • DOI: 10.1038/s41467-019-12232-3
  • NAID: 120006731596
  • Peer Reviewed / Open Access
• [Journal Article] The efficacy of a cyclin dependent kinase 9 (CDK9)inhibitor, FIT039, on verruca vulgaris: study protocol for a randomized controlled trial. (2019)
  • Author(s): Nomura T, Sumi E, Egawa G, Nakajima S, Toichi E, Uozumi R, Tada H, Nakagawa T, Hagiwara M, Kabashima K
  • Journal Title: Trials Volume: 20(1) Issue: 1 Pages: 489-489
  • DOI: 10.1186/s13063-019-3570-6
  • NAID: 120006796395
  • Peer Reviewed
• [Journal Article] Cutaneous p38 mitogen-activated protein kinase activation triggers psoriatic dermatitis. (2019)
  • Author(s): Sakurai K, Dainichi T, Garcet S, Tsuchiya S, Yamamoto Y, Kitoh A, Honda T, Nomura T, Egawa G, Otsuka A, Nakajima S, Matsumoto R, Nakano Y, Otsuka M, Iwakura Y, Grinberg-Bleyer Y, Ghosh S, Sugimoto Y, Guttman-Yassky E, Krueger JG, Kabashima K.
  • Journal Title: J Allergy Clin Immunol Volume: 144(4) Issue: 4 Pages: 1036-1049
  • DOI: 10.1016/j.jaci.2019.06.019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prostaglandin E(2) (PGE(2))-EP2signaling negatively regulates murine atopic dermatitis-like skin inflammation by suppressing thymic stromal lymphopoietin expression. (2019)
  • Author(s): Sawada Y, Honda T, Nakamizo S, Nakajima S, Nonomura Y, Otsuka A, Egawa G, Yoshimoto T, Nakamura M, Narumiya S, Kabashima K.
  • Journal Title: J Allergy Clin Immunol Volume: 144(5) Issue: 5 Pages: 1265-1273
  • DOI: 10.1016/j.jaci.2019.06.036
  • Peer Reviewed / Open Access
• [Journal Article] Percutaneous sensitization is limited by in situ inhibition of cutaneous dendritic cell migration through skin-resident regulatory T cells. (2019)
  • Author(s): Hanakawa S, Kitoh A, Shibuya R, Dainichi T, Nomura T, Honda T, Egawa G, Otsuka A, Nakajima S, Fujita M, Kabashima K.
  • Journal Title: J Allergy Clin Immunol. 2019 Volume: 144(5) Issue: 5 Pages: 1343-1353
  • DOI: 10.1016/j.jaci.2019.05.033
  • Peer Reviewed
• [Journal Article] Murine neonatal skin mast cells are phenotypically immature and minimally sensitized with transplacentally transferred IgE. (2019)
  • Author(s): Honda Y, Ono S, Honda T, Kataoka TR, Egawa G, Kitoh A, Otsuka A, Nakajima S, Nomura T, Dainichi T, Kabashima K.
  • Journal Title: J Allergy Clin Immunol. 2019 Volume: 144(2) Issue: 2 Pages: 617-620
  • DOI: 10.1016/j.jaci.2019.05.011
  • Peer Reviewed
• [Journal Article] Antigen presentation and adaptive immune responses in skin. (2019)
  • Author(s): Honda T, Egawa G, Kabashima K.
  • Journal Title: Int Immunol. Volume: 0 Issue: 7 Pages: 0-0
  • DOI: 10.1093/intimm/dxz005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intravital imaging of cutaneous immune responses (2018)
  • Author(s): Nakamizo Satoshi、Egawa Gyohei、Tan Kahbing Jasmine、Kabashima Kenji
  • Journal Title: Cellular Immunology Volume: - Pages: 103813-103813
  • DOI: 10.1016/j.cellimm.2018.05.006
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Expanded T cells under lymphopenic condition exhibits memory phenotype and infiltrate around hair follicle (2023)
  • Author(s): 石橋茉実、江川形平、椛島健治
  • Organizer: International Societies for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] The role of IL-23 in the pathogenesis of psoriasis : update your knowledge (2021)
  • Author(s): 江川形平
  • Organizer: 第50回日本免疫学会学術大会
  • Int'l Joint Research / Invited
• [Presentation] Revisiting the dogma of contact dermatitis; even single hapten application can induce allergic contact dermatitis in situ (2021)
  • Author(s): 江川形平
  • Organizer: 第46回日本研究皮膚科学会
  • Int'l Joint Research
• [Presentation] Itching mechanism in Atopic Dermatitis －from basic to clinical (2021)
  • Author(s): 江川形平
  • Organizer: 第46回日本研究皮膚科学会
  • Int'l Joint Research / Invited
• [Presentation] 乾癬病態の基礎的知見： 最近のトピックス (2021)
  • Author(s): 江川形平
  • Organizer: 第51回日本皮膚免疫アレルギー学会
  • Invited
• [Presentation] 末梢組織リンパ管を場とした免疫制御機構の解明 (2021)
  • Author(s): 江川形平
  • Organizer: 第120回日本皮膚科学会総会
• [Presentation] 皮膚免疫細胞の可視化 (2021)
  • Author(s): 江川形平
  • Organizer: 第120回日本皮膚科学会総会
  • Invited
• [Presentation] Two-photon microscopy_ its application to skin research (2019)
  • Author(s): 江川形平
  • Organizer: World Congress of Dermatology
  • Int'l Joint Research / Invited
• [Presentation] What skin barrier defect in atopic dermatitis teach us about epidermal physiology. (2019)
  • Author(s): 江川形平
  • Organizer: 日本研究皮膚科学会
  • Int'l Joint Research / Invited
• [Presentation] 皮膚のかゆみのメカニズム (2019)
  • Author(s): 江川形平
  • Organizer: 日本アレルギー学会学術大会
  • Invited
• [Presentation] 皮膚の防御における多段階的なT細胞の役割 (2019)
  • Author(s): 江川形平
  • Organizer: 日本臨床免疫学会
  • Invited
• [Book] Live Imaging of the Skin Immune Responses. (2020)
  • Author(s): Chow Z., Egawa G., Kabashima K.
  • Total Pages: 200
  • Publisher: Springer, Singapore
  • ISBN: 9789811379086
• [Book] 最新キーワードで読み解くALL About 皮膚科学＿ライブイメージング/二光子顕微鏡 (2019)
  • Author(s): 江川形平
  • Total Pages: 228
  • Publisher: メディカルレビュー社
  • ISBN: 9784779222351