FY2016 Annual Report

Immune Signal Unit

Assistant Professor Hiroki Ishikawa

Abstract

We have investigated molecular mechanisms of differentiation of immune cells which are associated with immunological diseases. T helper 17 (Th17) cells play a central role in many of autoimmune diseases. Cytokines TGF-b and IL-6 are required for the priming of Th17 differentiation, and another cytokine IL-23 is essential for generation of disease-causing Th17 cells. However, molecular mechanisms underlying IL-23-dependent regulation of Th17 pathogenicity remain largely unknown. In FY2016, we reported that an AP-1 transcription factor JunB is critical for IL-23-dependent generation of pathogenic Th17 cells.

1. Staff

  • Hiroki Ishikawa, Assistant Professor
  • Shin-ichi Koizumi, Postdoc
  • Daiki Sasaki, Postdoc
  • Naoyuki Taira, Postdoc
  • Hiroki Shirahata, Technician
  • Mio Miyagi, Technician
  • Tsung-Han Hsieh, Student
  • Shukla Sarker, Student
  • Ke Wang, Student
  • Tsung-Yen Huang, Student
  • Hsiao-Chiao Hsieh, Student
  • Rika Yoshizawa, Research Unit Administrator

2. Collaborations

        Nothing to report.

 

3. Activities and Findings

 

IL-17-producing Th17 cells comprise heterogeneous subsets exhibiting distinct pathogenicity. Although pathogenic and non-pathogenic Th17 subsets share a common Th17 transcriptional program composed of BATF, IRF4, STAT3, and RORgt, transcriptional regulatory mechanisms specific to each of these distinct Th17 subsets remain largely unknown. We have reported that an AP-1 transcription factor, JunB, is essential for induction of RORgt by facilitating DNA-binding of BATF, IRF4 and STAT3 at the Rorc locus in IL-23-dependent pathogenic Th17 cells, but not in TGF-b1-dependent non-pathogenic Th17 cells. Indeed, Junb-deficient T cells lose their ability to induce Th17-mediated experimental autoimmune encephalomyelitis (EAE) and colitis, but gut-resident Th17 cells are probably generated in a JUNB-independent manner. The selective requirement of JUNB for pathogenic Th17 differentiation suggests that the JUNB-dependent pathway may be a specific therapeutic target for autoimmune and chronic inflammatory diseases.

 

Fig. 2. JunB is critical for pathogenic Th17 differentiation, but not non-pathogenic Th17 cells.

Upon antigen recognition, naïve T-cell differentiates into non-pathogenic or pathogenic Th17 cell in the presence of TGF-b + IL-6 or IL-23 + IL-6 + IL-1b cytokines, respectively. Non-pathogenic Th17 cells are important for gut homeostasis and host defense. In contrast, pathogenic Th17 cells cause autoimmunity. Our study demonstrated that JunB is specifically required for pathogenic Th17 differentiation.

 

4. Publications

4.1 Journals

  1. Hasan Z, Koizumi S, Sasaki D, Yamada H, Arakaki N, Fujihara Y, Okitsu S, Shirahata S, and Ishikawa H, JunB is essential for IL-23-dependent pathogenicity of Th17 cells. (2017) Nat. commun. 15628

4.2 Books and other one-time publications

Nothing to report

4.3 Oral and Poster Presentations

  1. Hiroki Ishikawa, JUNB is required for generation of pathogenic Th17 cells. The 2nd JST-SICORP /The 6th Ortho-Organogenesis Joint Workshop, Okinawa, Dec 7-9, 2016.
  2. Hiroki Ishikawa, JunB facilitates IL-23-dependent pathogenic Th17 differentiation. The 45th Annual Meeting of The Japanese Society for Immunology, Okinawa, Dec 5-7, 2016.
  3. Hiroki Ishikawa, JunB-dependent regulation of pathogenicity of Th17 cells. The 2nd Design Biotechnology meeting, Kobe, Mar 21, 2017.

5. Intellectual Property Rights and Other Specific Achievements

Nothing to report

6. Meetings and Events

Nothing to report

7. Other

Nothing to report.