抗原提示細胞の機能的分化を制御する分子基盤の解明

2022 Fiscal Year Annual Research Report

• Project/Area Number: 20H03505
• Research Institution: Wakayama Medical University
• Principal Investigator: 改正 恒康 和歌山県立医科大学, 先端医学研究所, 教授 (60224325)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 樹状細胞 / I型インターフェロン / DNAセンサー / プロテアソーム / 自己炎症 / 免疫不全

Outline of Annual Research Achievements

自己炎症性疾患患者において同定された遺伝子変異（バリアント）を導入したマウスについて免疫学的解析を行った。
まず、タンパク質の細胞内輸送を担う機能分子COPAにアミノ酸置換を来す新規遺伝子バリアント（COPA p.V242G）をヘテロで有するマウスの解析を進めた。樹状細胞において、細胞質内DNAセンサー経路（STING）は亢進していたが、細胞質内RNAセンサー経路（RIG-I）、膜タンパクを介した核酸センサー経路（TLR7/9）はむしろ抑制されていた。また、間質性肺炎の病変部位では、脾臓と同様に、I型インターフェロン（IFN）で誘導される遺伝子群の発現が亢進されていて、T細胞については、CD4T細胞、CD8T細胞共に、顕著な活性化とIFN-γの産生亢進が認められた。
また、プロテアソームサブユニットβ1iのアミノ酸置換を引き起こす新規遺伝子バリアント（β1i p.G156D）をヘテロで有するマウスにおいては、リンパ球と共に樹状細胞が減少していた。樹状細胞については、I型、II型通常樹状細胞（CDC1、CDC2）、形質細胞様樹状細胞（PDC）、すべてのサブセットが減少していたが、特にCDC1の減少が顕著であった。この傾向は骨髄細胞をサイトカイン（Flt3L）存在下で培養した樹状細胞についても認められた。また、樹状細胞前駆細胞について、数はほぼ正常であったが、いくつかの分化マーカーの発現低下が認められ、この分化段階で異常が生じていることが示唆された。さらに、好中球、単球については、数は増加していたが、特に脾臓での成熟分化が障害されていた。このように、β1i p.G156Dによって生じる免疫機構の破綻の実態が明らかになってきた。

Research Progress Status

令和4年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和4年度が最終年度であるため、記入しない。

Remarks

免疫不全を伴うプロテアソーム関連自己炎症症候群の発見とそのモデルマウスhttps://www.wakayama-med.ac.jp/intro/press/r3/211207/07_menekifuzen.html
COPA症候群（自己炎症性疾患）モデルマウス　https://www.wakayama-med.ac.jp/intro/press/r3/210628/28_seitai.html

Research Products

• [Int'l Joint Research] Yale Univ./Harverd Medical School/Emory Univ.(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Yale Univ./Harverd Medical School/Emory Univ.
  • # of Other Institutions: 35
• [Int'l Joint Research] Univ. of Melbourne/Australia National Univ./Telethon Kids Institute(オーストラリア)
  • Country Name: AUSTRALIA
  • Counterpart Institution: Univ. of Melbourne/Australia National Univ./Telethon Kids Institute
  • # of Other Institutions: 1
• [Int'l Joint Research] Mainz Univ./Univ. Hospital Wuerzburg/Univ. Hostital Cologne(ドイツ)
  • Country Name: GERMANY
  • Counterpart Institution: Mainz Univ./Univ. Hospital Wuerzburg/Univ. Hostital Cologne
  • # of Other Institutions: 15
• [Int'l Joint Research] London Research Institute/Imperial College/Cardiff Univ.(英国)
  • Country Name: UNITED KINGDOM
  • Counterpart Institution: London Research Institute/Imperial College/Cardiff Univ.
  • # of Other Institutions: 1
• [Int'l Joint Research] San Raffaele Scientific Institute/ICGEB(イタリア)
  • Country Name: ITALY
  • Counterpart Institution: San Raffaele Scientific Institute/ICGEB
• [Int'l Joint Research]
  • # of Other Countries: 10
• [Journal Article] Conventional Type 1 dendritic cells in intestinal immune homeostasis. (2022)
  • Author(s): I. Sasaki, T. Kato, H. Hemmi, Y. Fukuda-Ohta, N. Wakaki-Nishiyama, A. Yamamoto, T. Kaisho.
  • Journal Title: Front Immunol Volume: 13 Pages: 857954
  • DOI: 10.3389/fimmu.2022.857954
  • Peer Reviewed / Open Access
• [Journal Article] Preparation and Inflammasome Activation of Murine Bone Marrow-Derived and Resident Peritoneal Macrophages. (2022)
  • Author(s): I. Sasaki, T. Kaisho.
  • Journal Title: Methods Mol Biol Volume: 2427 Pages: 95-104
  • DOI: 10.1007/978-1-0716-1971-1_9
  • Peer Reviewed
• [Journal Article] Type 1 conventional dendritic cells maintain and guide the differentiation of precursors of exhausted T cells in distinct cellular niches. (2022)
  • Author(s): S. Daehling, A. M. Mansilla, K. Knopper, A. Grafen,D. T Utzschneider, M. Ugur, P. G Whitney, A. Bachem, P. Arampatzi, F. Imdahl, T. Kaisho, D. Zehn, F. Klauschen, N. Garbi, A. Kallies, A.-E. Saliba, G. Gasteiger, S. Bedoui, W. Kastenmuller.
  • Journal Title: Immunity Volume: 55 Pages: 656-670
  • DOI: 10.1016/j.immuni.2022.03.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Distinct myeloid antigen-presenting cells dictate differential fates of tumor-specific CD8+ T cells in pancreatic cancer. (2022)
  • Author(s): A. L. Burrack, Z. C. Schmiechen, M. T. Patterson, E. A. Miller, E. J. Spartz, M. R. Rollins, J. F. Raynor, J. S. Mitchell, T. Kaisho, B. T. Fife, I. M. Stromnes.
  • Journal Title: JCI Insight Volume: 7 Pages: e151593
  • DOI: 10.1172/jci.insight.151593
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The liver contains distinct interconnected networks of CX3CR1+ macrophages, XCR1+ type 1 and CD301a+ type 2 conventional dendritic cells embedded within portal tracts. (2022)
  • Author(s): K. English, S. Yang Tan, R. Kwan, L. E Holz, F. Sierro, C. McGuffog, T. Kaisho, W. R Heath, K. Pa MacDonald, G. W McCaughan, D. G Bowen, P. Bertolino.
  • Journal Title: Immunol Cell Biol Volume: 100 Pages: 394-408
  • DOI: 10.1111/imcb.12559
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A vaccine targeting resistant tumours by dual T cell plus NK cell attack. (2022)
  • Author(s): S. Badrinath, MO. Dellacherie, A. Li, S. Zheng, X. Zhang, M. Sobral, JW. Pyrdol, KL. Smith, Y. Lu, S. Haag, H. Ijaz, F. Connor-Stroud, T. Kaisho, G. Dranoff, GC. Yuan, DJ. Mooney, KW. Wucherpfennig.
  • Journal Title: Nature Volume: 606 Pages: 992-998
  • DOI: 10.1038/s41586-022-04772-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Thymic epithelial cells co-opt lineage-defining transcription factors to eliminate autoreactive T cells. (2022)
  • Author(s): D. A Michelson, K. Hase, T. Kaisho, C. Benoist, D. Mathis.
  • Journal Title: Cell Volume: 185 Pages: 2542-2558
  • DOI: 10.1016/j.cell.2022.05.018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Depletion of cDC1 cells upon immunotherapy of established tumors precludes efficacy. (2022)
  • Author(s): A. Teijeira, S. Garasa, C. luri, C. de Andrea, M. Gato, C. Molina, T. Kaisho, A. Cirella, A. Azpilikueta, S. Wculek, J. Egea, I. Olivera, I. Rodriguez, A. Rouzaut, V. Verkhusha, K. Valencia, D. Sancho, P. Berraondo, I. Melero.
  • Journal Title: Cancer Research Volume: 82 Pages: 4373-4385
  • DOI: 10.1158/0008-5472.CAN-22-1046
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Spi-B alleviates food allergy by securing mucosal barrier and immune tolerance in the intestine. (2022)
  • Author(s): N. Ishihara,Y. Nakamura, K. Yakabe, S. Komiyama, Y. Fujimura, T. Kaisho, S. Kimura, K. Hase.
  • Journal Title: Front Allergy Volume: 3 Pages: 996657
  • DOI: 10.3389/falgy.2022.996657
  • Peer Reviewed / Open Access
• [Journal Article] Tmem45b is essential for inflammation- and tissue injury-induced mechanical pain hypersensitivity. (2022)
  • Author(s): T. Tanioku, M. Nishibata, Y. Tokinaga, K. Konno, M. Watanabe, H. Hemmi, Y. Fukuda-Ohta, T. Kaisho, H. Furue, T. Kawamata.
  • Journal Title: Proc Natl Acad Sci USA Volume: 119 Pages: e2121989119
  • DOI: 10.1073/pnas.2121989119
  • Peer Reviewed / Open Access
• [Journal Article] Androgen-regulated MafB drives cell migration via MMP11-dependent extracellular matrix remodeling in mice. (2022)
  • Author(s): M.C. Alcantara, K. Suzuki, AR. Acebedo, D. Kajioka, S. Hirohata,T. Kaisho, Y. Hatano, K. Yamagata, S. Takahashi, G. Yamada.
  • Journal Title: iScience Volume: 25 Pages: 105609
  • DOI: 10.1016/j.isci.2022.105609
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] XCR1+ DCs are critical for T cell-mediated immunotherapy of chronic viral infections. (2022)
  • Author(s): E. Domenjo Vila, V. Casella, R. Iwabuchi, E. Fossum, M. Pedragosa, Q. Castellvi, P. Cebollada Rica, T. Kaisho, K. Terahara, G. Bocharov, J. Argilaguet, A. Meyerhans.
  • Journal Title: Cell Rep Volume: 42 Pages: 112123
  • DOI: 10.1016/j.celrep.2023.112123
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 免疫不全を伴うプロテアソーム関連自己炎症症候群. Proteasome-associated autoinflammatory syndrome with immunodeficiency. (2022)
  • Author(s): 改正恒康
  • Journal Title: アレルギーの臨床 Volume: 43 Pages: 30-34
• [Presentation] Hypomorphic mutation of Lig4 gene in mice predisposes to intestinal inflammation driven by Th1 cells (2022)
  • Author(s): Y. Yamashita, T. Kato, H. Kosako, S. Iwabuchi, K. Tanaka, K. Nakashima, I. Sasaki, S. Hashimoto, K. Ohshima, T. Kaisho, T. Sonoki, S. Tamura.
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] Model mice of human inborn errors of immunity showing mixed manifestations of aouoinflammation,immunodeficiency and/or autoimmunity. (2022)
  • Author(s): T. Kaisho
  • Organizer: 第51回日本免疫学会総会・学術集会
  • Invited
• [Presentation] γδT cells in Peyer’s patches acquire the encephalitogenic phenotype through the activation by commensals and exacerbates autoimmune ncephaomyelitis. (2022)
  • Author(s): S. Komiyama, D. Takahashi, T.Kaisho, K. Hase.
  • Organizer: 第51回日本免疫学会総会・学術集会
• [Presentation] Dendritic and T cell abnormalities in an autoinflammatory disease with interstitial lung disease and type 1 interferonopathy caused by a disability of retrongrade protein trafficking. (2022)
  • Author(s): T. Kato, I.Sasaki, H. Hemmi, Y. Honda. K. Izawa, R. Nishikomori, T. Kaisho.
  • Organizer: 第51回日本免疫学会総会・学術集会
• [Presentation] Type 1 conventional dendritic cells of bone marrow assistthe prograession of multiple myeloma and consist of tumor microenvironment in the transplanted Vk*MYC mouse model. (2022)
  • Author(s): S.Suzuki, S.Tsuda, T.Takubo, H.Toyoshima, M.Yoshino, T.Kaisho, T.Fukuda, K.Tokoyoda.
  • Organizer: 第51回日本免疫学会総会・学術集会
• [Presentation] The role of Rnase T2 in macrophage homeostasis. (2022)
  • Author(s): R. Sato, K.Liu, T.Shibata, R.Fukui, K.Hoshino, T.Kaisho, K.Miyake.
  • Organizer: 第51回日本免疫学会総会・学術集会
• [Presentation] 遺伝子改変マウスを用いた組織常在マクロファージの免疫学的解析 (2022)
  • Author(s): 加治汐梨、佐々木泉、加藤喬、西山奈央子、山本明日美、脇村一輝、北野雅之、改正恒康
  • Organizer: 第29回日本免疫毒性学会学術年会
• [Presentation] Activation of type 1 interferon signaling in dendritic cells and T cells of the mouse model of COPA syndrome. (2022)
  • Author(s): T.Kato, R.Yamasaki, N.W-Nishiyama. I.Sasaki, S.Kaji, K.Murakami, H.Hemmi, Y.Honda, K.Izawa, Y.Otsuki, T.Matsubayashi, R.Nishikomori, T.Kaisho.
  • Organizer: 第29回日本免疫毒性学会学術年会
• [Presentation] Lig4遺伝子の低形成性変異を有したマウスは異常Th1細胞による炎症性腸疾患を発症する (2022)
  • Author(s): 田村志宜、山下友佑、小浴秀樹、加藤喬、岩淵貞弘、佐々木泉、橋本真一、改正恒康
  • Organizer: 第6回日本免疫不全・自己炎症学会総会・学術集会
• [Presentation] Immunotherapy of chronic virus infections: exhausted CD8+ T cell subsets are differentially regulated by XCR1+ DC. (2022)
  • Author(s): A.Meyerhans, E.D-Vila, V.Casella, R.Iwabuxhi, E.Fossum, M.Pedragosa, Q.Castellvi, T.Kaisho, K.Terahara, G.Bocharov, J.Argilaguet.
  • Organizer: The 16th International Symposium on Dendritic Cells 2022
  • Int'l Joint Research
• [Presentation] γδT17 cells in Peyer’s patches acquire the encephalitogenic phenotype through the activation by commensals. (2022)
  • Author(s): S. Komiyama, D. Takahashi, T. Kaisho, H. Watarai, K. Hase.
  • Organizer: The 9th Congress of International Human Microbiome Consortium
  • Int'l Joint Research