Regulation of Hepatitis B Virus-Specific T Cell Responses by Innate Immune Response

• Project/Area Number: 17K09436
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Nagoya City University
• Principal Investigator: Isogawa Masanori 名古屋市立大学, 医薬学総合研究院(医学), 講師 (50723201)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: B型肝炎ウイルス / CD8＋T細胞 / 自然免疫 / HBV / IFN / CD8+T細胞 / T細胞 / インターフェロン / T細胞応答

Outline of Final Research Achievements

In this study, we investigated the role of type I interferon (IFN) in the induction of HBV-specific CD8 + T cell responses. In a transient HBV infection model, we showed that type I IFN indirectly attenuates HBV-specific CD8 + T cell response by suppressing the amount of antigen in the early stage of HBV transduction. On the other hand, in the persistent HBV infection model, we showed that antigen recognition in the liver suppresses the type I IFN signal in CD8 + T cells, and that its activation is extremely important for the induction of T cell proliferation and functionality

Academic Significance and Societal Importance of the Research Achievements

全世界でおよそ2億5千万人がHBVに持続感染しており、肝細胞癌へと進行するリスクにさらされている。HBVの排除にはHBV特異的CD8+T細胞応答が必要不可欠である。I型IFNがHBV特異的CD8+T細胞に及ぼす影響はほとんど理解されておらず、本研究は学術的に極めて意義深い。さらに、T細胞内のI型IFNシグナルを活性化することでT細胞の増殖と機能性の誘導ができるという成果は、B型慢性肝炎に対する新たな治療法の確立に役立つと考えられ、その社会的意義も非常に大きい。

Research Products

• [Int'l Joint Research] The Scripps Research Institute(米国)
• [Int'l Joint Research] Alaska Native Tribal Health Consortium(米国)
• [Journal Article] The antiviral effects of human microRNA miR-302c-3p against hepatitis B virus infection (2019)
  • Author(s): Hamada-Tsutsumi Susumu、Naito Yutaka、Sato Seiichi、Takaoka Akinori、Kawashima Keigo、Isogawa Masanori、Ochiya Takahiro、Tanaka Yasuhito
  • Journal Title: Alimentary Pharmacology & Therapeutics Volume: 49 Issue: 8 Pages: 1060-1070
  • DOI: 10.1111/apt.15197
  • Peer Reviewed
• [Journal Article] Small Interfering RNA Screening for the Small GTPase Rab Proteins Identifies Rab5B as a Major Regulator of Hepatitis B Virus Production (2019)
  • Author(s): Inoue Jun、Ninomiya Masashi、Umetsu Teruyuki、Nakamura Takuya、Kogure Takayuki、Kakazu Eiji、Iwata Tomoaki、Takai Satoshi、Sano Akitoshi、Fukuda Mitsunori、Watashi Koichi、Isogawa Masanori、Tanaka Yasuhito、Shimosegawa Tooru、McNiven Mark A.、Masamune Atsushi
  • Journal Title: Journal of Virology Volume: 93 Issue: 15
  • DOI: 10.1128/jvi.00621-19
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Designing a therapeutic hepatitis B vaccine to circumvent immune tolerance (2019)
  • Author(s): Whitacre DC、Peters CJ、Sureau C、Nio K、Li F、Su L、Jones JE、Isogawa M、Sallberg M、Frelin L、Peterson DL、Milich DR
  • Journal Title: Human Vaccines & Immunotherapeutics Volume: 16 Issue: 2 Pages: 251-268
  • DOI: 10.1080/21645515.2019.1689745
  • Peer Reviewed
• [Journal Article] Functional cureをめざすB型肝炎治療の近未来 (2019)
  • Author(s): 五十川正記, 田中靖人
  • Journal Title: 医学のあゆみ Volume: 268(4) Pages: 282-3
• [Journal Article] Intrahepatic Cross-Presentation and Hepatocellular Antigen Presentation Play Distinct Roles in the Induction of HBV-Specific CD8+ T Cell Responses (2018)
  • Author(s): Murata Yasuhiro, Kawashima Keigo, Sheikh Knvul, Tanaka Yasuhito, Isogawa Masanori
  • Journal Title: Journal of Virology Volume: 92 (21) Issue: 21 Pages: 00920-18
  • DOI: 10.1128/jvi.00920-18
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Type I Interferon Signaling Prevents Hepatitis B Virus-Specific T Cell Responses by Reducing Antigen Expression (2018)
  • Author(s): Kawashima Keigo, Isogawa Masanori, Hamada-Tsutsumi Susumu, Baudi Ian, Saito Satoru, Nakajima Atsushi, Tanaka Yasuhito
  • Journal Title: Journal of Virology Volume: 92 (23) Issue: 23 Pages: 01099-18
  • DOI: 10.1128/jvi.01099-18
  • Peer Reviewed / Open Access
• [Journal Article] An Association Between Core Mutations in Hepatitis B Virus Genotype F1b and Hepatocellular Carcinoma in Alaskan Native People (2018)
  • Author(s): Hayashi Sanae, Khan Anis, Simons Brenna C., Homan Chriss, Matsui Takeshi, Ogawa Kenji, Kawashima Keigo, Murakami Shuko, Takahashi Satoru, Isogawa Masanori, Ikeo Kazuho, Mizokami Masashi, McMahon Brian J., Tanaka Yasuhito
  • Journal Title: Hepatology Volume: 69 (1) Issue: 1 Pages: 19-33
  • DOI: 10.1002/hep.30111
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] B型肝炎に対する免疫治療の展望 (2018)
  • Author(s): 五十川正記, 田中靖人
  • Journal Title: Medical Science Digest Volume: 44(7) Pages: 344-49
• [Journal Article] なぜHBV排除は困難なのか (2018)
  • Author(s): 五十川正記, 田中靖人
  • Journal Title: Mebio Volume: 35 Pages: 4-13
• [Presentation] The role of intrahepatic type I interferon signaling in HBV-specific T cell responses (2019)
  • Author(s): Isogawa M
  • Organizer: APASL Single Topic Conference in Tokyo “Liver Immunology and Genetics”
  • Int'l Joint Research / Invited
• [Presentation] IFNα directly induces apoptosis in hepatocytes that accumulate hepatitis B large S proteins (2019)
  • Author(s): Baudi I, Isogawa M, Kawashima K, Tanaka Y
  • Organizer: APASL Single Topic Conference in Tokyo “Liver Immunology and Genetics”
  • Int'l Joint Research
• [Presentation] The role of intrahepatic type I interferon signaling in HBV-specific T cell responses (2019)
  • Author(s): Kawashima K, Isogawa M, Saito S, Nakajima A, Tanaka Y
  • Organizer: APASL Single Topic Conference in Tokyo “Liver Immunology and Genetics”
  • Int'l Joint Research
• [Presentation] OX40シグナル刺激によるHBV排除の試み～HBV特異的CD8+T細胞の選択的活性化～ (2019)
  • Author(s): 河島圭吾, 五十川正記, 田中靖人
  • Organizer: 第55回日本肝臓学会総会
• [Presentation] 肝臓内インターフェロンシグナル活性化によるHBV排除の試み (2019)
  • Author(s): 河島圭吾, 五十川正記, 大西雅也, 田中靖人
  • Organizer: 第29回抗ウイルス療法学会学術集会・総会
• [Presentation] OX40 signaling activation selectively differentiates CD8 T cells recognizing HBV antigens in the liver (2019)
  • Author(s): Kawashima K，Isogawa M，Onishi M，Tanaka Y
  • Organizer: 2019 International HBV Meeting
  • Int'l Joint Research
• [Presentation] 14.Potential role of unfolded protein responses in IFN-mediated liver injury during HBV infection (2019)
  • Author(s): Baudi I, Isogawa M, Kawashima K, Tanaka Y
  • Organizer: The 70th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2019)
  • Int'l Joint Research
• [Presentation] Type I interferon signaling prevents hepatitis B virus-specific T cell responses by reducing antigen expression (2018)
  • Author(s): Kawashima K, Isogawa M, Tsutsumi S, Saito S, Nakajima A, Tanaka Y
  • Organizer: Taiwan-Japan-Korea HBV Research Symposium 2018
  • Int'l Joint Research
• [Presentation] A Novel Association Between Core Mutations in Hepatitis B Virus Genotype F1b and HCC in Alaskan Native People (2018)
  • Author(s): Hayashi S, Khan A, Simons BC, Homan C, Matsui T, Ogawa K, Kawashima K, Murakami S, Takahashi S, Isogawa M, Ikeo K, Mizokami M, McMahon BJ, Tanaka Y
  • Organizer: APASL Single Topic Conference on HCC
  • Int'l Joint Research
• [Presentation] ヒト肝細胞キメラマウスを用いた長期CFCP投与による抗HBV効果～cccDNAは低下するか？～ (2018)
  • Author(s): 林佐奈衣, 鍬田伸好, 熊本浩樹, 村上周子, 尾曲克己, 五十川正記, 前田賢次, 満屋裕明, 田中靖人
  • Organizer: 第28回抗ウイルス療法学会学術集会・総会
• [Presentation] HBV排除における肝臓内インターフェロンシグナル誘導の重要性 (2018)
  • Author(s): 河島圭吾, 五十川正記, 田中靖人
  • Organizer: 第54回日本肝臓学会総会
• [Presentation] Highly accurate quantification of intrahepatic Hepatitis B virus cccDNA by droplet digital PCR (2018)
  • Author(s): Hayashi S，Ito K，Isogawa M，Tanaka Y，Kawashima K
  • Organizer: The 2018 International HBV Meeting The Molecular Biology of Hepatitis B Viruses
  • Int'l Joint Research
• [Presentation] Activation of type I interferon signaling is required for the induction of functional HBV-specific CD8 T cells (2018)
  • Author(s): Kawashima K，Isogawa M，Saito S，Nakajima A，Tanaka Y
  • Organizer: The 2018 International HBV Meeting The Molecular Biology of Hepatitis B Viruses
  • Int'l Joint Research
• [Presentation] Akt signaling triggers expansion of intrahepatic effector CD8+ T cells and drives protective immunity against persistent HBV infection (2018)
  • Author(s): Huang LR, Chen YJ, Hsu SC, Hsu DW, Pong CY, Su YC, Knolle P, Isogawa M
  • Organizer: The 2018 International HBV Meeting The Molecular Biology of Hepatitis B Viruses
  • Int'l Joint Research
• [Presentation] Critical role of hepatic antigen presentation in the expansion of hepatitis B virus-specific CD8+ T cells (2018)
  • Author(s): Isogawa M
  • Organizer: 2018 US-Japan Hepatitis Panel Meeting,
  • Int'l Joint Research / Invited
• [Presentation] HBV特異的CD8+T細胞応答誘導における肝細胞の役割 (2018)
  • Author(s): 五十川正記, 村田泰洋, 田中靖人
  • Organizer: 第32回肝類洞壁細胞研究会学術集会
• [Presentation] Reduction of Hepatitis B Virus (HBV) Gene Expression in the Liver Induces Functional HBV-specific CD8 T Cell Responses without Liver Disease (2017)
  • Author(s): Kawashima K, Isogawa M, Tanaka Y
  • Organizer: 5th JAPAN-TAIWAN-KOREA HBV Research Symposium 2017
  • Int'l Joint Research
• [Presentation] Intrahepatic Stimulation of RIG-I Like Receptors (RLR) Induces HBV-Specific Cytotoxic T Cell Responses and Suppresses HBV Gene Expression (2017)
  • Author(s): Isogawa M, Kawashima K, Tanaka Y
  • Organizer: 5th JAPAN-TAIWAN-KOREA HBV Research Symposium 2017
  • Int'l Joint Research
• [Presentation] I型インターフェロンシグナルは肝臓内HBV特異的CD8+T細胞応答を阻害する (2017)
  • Author(s): 河島圭吾, 五十川正記, 田中靖人
  • Organizer: 第103回日本消化器病学会総会
• [Presentation] Entecavirよりも持続的かつ強力に抗HBV活性を有する新規核酸アナログCFCPの同定 (2017)
  • Author(s): 林佐奈衣, 鍬田伸好, 熊本浩樹, 村上周子, 尾曲克己, 五十川正記, 前田賢次, 満屋裕明, 田中靖人
  • Organizer: 第27回抗ウイルス療法学会学術集会
• [Presentation] 肝臓内RIG-I Like Receptors (RLR)刺激による効率的なHBV抑制 (2017)
  • Author(s): 河島圭吾, 五十川正記, 田中靖人
  • Organizer: 第27回抗ウイルス療法学会学術集会
• [Presentation] 肝臓内HBV特異的CD8+T細胞応答はI型インターフェロンシグナルにより制御される (2017)
  • Author(s): 河島圭吾, 五十川正記, 田中靖人
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] I型インターフェロンはHBV Large S 抗原を蓄積した肝細胞の細胞死を誘導する (2017)
  • Author(s): 五十川正記, 河島圭吾, 田中靖人
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] Type I interferon signaling prevents hepatitis B virus-specific T cell responses (2017)
  • Author(s): Kawashima K, Isogawa M, Tsutsumi S, Saito S, Nakajima A, Tanaka Y
  • Organizer: The 2017 International HBV Meeting
  • Int'l Joint Research
• [Presentation] Type 1 Interferon Signaling Induces Cell Death in Hepatocytes That Accumulate the Large Hepatitis B Surface Antigen (2017)
  • Author(s): Baudi I, Isogawa M, Kawashima K, Tanaka Y
  • Organizer: The 2017 International HBV Meeting
  • Int'l Joint Research
• [Presentation] Accumulation of the Large Hepatitis B Surface Antigen Predisposes Hepatocytes to IFNα Mediated Cell Death (2017)
  • Author(s): Baudi I, Isogawa M, Kawashima K, Tanaka Y
  • Organizer: The 68th Annual Meeting of the American Association for the Study of Liver Diseases
  • Int'l Joint Research
• [Presentation] Hepatitis B Virus-specific T Cell Responses Are Regulated by Type I Interferon Signaling and Correlated with Intrahepatic Antigen Expression (2017)
  • Author(s): Kawashima K, Isogawa M, Hamada-Tsutsumi S, Saito S, Tanaka Y
  • Organizer: The 68th Annual Meeting of the American Association for the Study of Liver Diseases
  • Int'l Joint Research
• [Presentation] Hepatocytes Retaining the Large Hepatitis B Surface Antigen (LHBs) are Susceptible to the Cytotoxic Effect of Type I Interferons (2017)
  • Author(s): Isogawa M，Baudi I，Kawashima K，Tanaka Y
  • Organizer: 第65回日本ウイルス学会学術集会
  • Int'l Joint Research
• [Presentation] 肝臓内RIG-I Like Receptors（RLR）刺激によるB型肝炎ウイルス（HBV）特異的CD8+T細胞応答の誘導, (2017)
  • Author(s): 五十川正記, 河島圭吾, 田中靖人
  • Organizer: 第42回日本肝臓学会西部会