Understanding of the mechanism for inducing IFNgamma-producing CD8T cells in the gut

• Project/Area Number: 16K19165
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Immunology
• Research Institution: Keio University (2017-2018); Institute of Physical and Chemical Research (2016)
• Principal Investigator: Tanoue Takeshi 慶應義塾大学, 医学部(信濃町), 講師 (60732972)
• Research Collaborator: SUDA Wataru
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: Microbiota / CD8T / IFNgamma / 腸内細菌 / CD8 T細胞

Outline of Final Research Achievements

In this study, we found that interferon-gamma; (IFNγ)-producing CD8+ T cells were highly abundant in the intestine of specific pathogen-free (SPF) mice and which were driven by microbiota. This is because IFNγ+CD8+ T cells were severly depleted in germ-free (GF) mice and SPF mice treated with antibiotics-mixture, and we could see the induction by oral inoculation of GF mice with SPF feces. Specific members of microbiota were corresponded to induce IFNγ+CD8+ T cell since the relative abundance of this cell population in SPF mice varied with housing conditions, and co-housing resulted in all mice ultimately displaying a high-frequency phenotype. Using our bacterial isolate which robustly induce IFNγ+CD8+ T cells in intestines, repetitive administrations of the mixture enhanced host resistance against Listeria monocytogenes infection.

Academic Significance and Societal Importance of the Research Achievements

IFNγ産生CD8T細胞を強く誘導する我々の単離菌カクテルを経口投与すると、CD8T細胞依存的にリステリアモノサイトゲネス感染症の症状が緩和されたことから、IFNγ産生CD8T細胞は病原性微生物感染に対する抵抗性を強めることが示唆された。このことから、腸内常在菌によって誘導されたIFNγ産生CD8T細胞は腸管での微生物感染に対するバリア機能に貢献していることが推察され、同細胞を介した新しい感染症治療法の開発に繋がる可能性が考えられる。

Research Products

• [Journal Article] Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation" Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammationx (2017)
  • Author(s): Atarashi K, Suda W, Luo C, Kawaguchi T, Motoo I, Narushima S, Kiguchi Y, Yasuma K, Watanabe E, Tanoue T, Thaiss CA, Sato M, Toyooka K, Said HS, Yamagami H, Rice SA, Gevers D, Johnson RC, Segre JA, Chen K, Kolls JK, Elinav E, Morita H, Xavier RJ, Hattori M, Honda K.
  • Journal Title: Science Volume: 358 Issue: 6361 Pages: 359-365
  • DOI: 10.1126/science.aan4526
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Helicobacterspecies are potent drivers of colonic T cell responses in homeostasis and inflammation (2017)
  • Author(s): Chai Jiani N.、Peng Yangqing、Rengarajan Sunaina、Solomon Benjamin D.、Ai Teresa L.、Shen Zeli、Perry Justin S. A.、Knoop Kathryn A.、Tanoue Takeshi、Narushima Seiko、Honda Kenya、Elson Charles O.、Newberry Rodney D.、Stappenbeck Thaddeus S.、Kau Andrew L.、Peterson Daniel A.、Fox James G.、Hsieh Chyi-Song
  • Journal Title: Science Immunology Volume: 2 Issue: 13
  • DOI: 10.1126/sciimmunol.aal5068
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 腸内フローラとTH17細胞 (2017)
  • Author(s): 田之上 大、新 幸二、本田 賢也
  • Journal Title: Clinical Neuroscience Volume: 35 Pages: 1290-1292
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] 腸管IFNg産生CD8T細胞を誘導するヒト常在細菌種の同定 (2017)
  • Inventor(s): 本田賢也、田之上大、服部正平
  • Industrial Property Rights Holder: 本田賢也、田之上大、服部正平
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017-02-10
  • Overseas