FY2018 Annual Report

Immune Signal Unit

Assistant Professor Hiroki Ishikawa


Research in our unit has focused on molecular mechanisms of differentiation of immune cells. We are particularly interested in transcriptional regulatory mechanisms of T cell differentiation. Our recent data clearly demonstrate important roles for the AP-1 transcription factor JunB in the functional diversification of T cell subsets. In this fiscal year, we found that JunB promotes differentiation and suppressive functions of effector T regulatory cells.


1. Staff

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


2. Collaborations

Nothing to report.


3. Activities and Findings

Foxp3-expressing Treg cells are essential for the maintenance of immune homeostasis. Treg cells need to differentiate into effector Treg (eTreg) cells to accumulate in peripheral tissues and exert their suppressive functions. Although T cell receptor (TCR)-stimulation-induced IRF4 is required for eTreg differentiation, how the transcriptional activity of IRF4 is regulated in eTreg differentiation remains largely unknown. We found that JunB was highly expressed in CD44hi eTreg cells, but not in CD62LhiCD44lo conventional Treg (cTreg) cells. JunB expression was upregulated by co-stimulatory and IL-2 signals upon TCR stimulation. Treg-specific Junb-deficient mice (Treg-JunB KO; Junbfl/flFoxp3Cre) developed multi-organ autoimmunity, concomitant with abnormal expression of inflammatory cytokines in T helper cells and elevated production of immunoglobulins. In Treg-JunB KO mice, eTreg cells were generated normally in most peripheral tissues, although they were significantly decreased in the gut. However, in vitro and in vivo suppression assays showed that the suppression activity of Junb-deficient eTreg cells was severely impaired. RNA-sequencing analysis revealed that JunB regulates the expression of a subset of eTreg-related genes, such as Icos and Ctla4, in BATF-dependent and BATF-independent manners. ChIP-seq analysis indicated that JunB promoted DNA-binding of IRF4 at 30% of IRF4 target sites. These data demonstrate that the JunB-dependent modulation of IRF4 activity is needed for eTreg cells to accumulate in the gut and for their full suppressive function.


4. Publications

4.1. Publications

Koizumi S, Sasaki D, Hsieh T, Taira N, Arakaki N, Yamasaki S, Wang K, Sarkar S, Shirahata H, Miyagi M, and Ishikawa H (2018) JunB regulates homeostasis and suppressive functions of effector regulatory T cells. Nat. commun. 9, 5344.

4.2. Oral and poster presentation

Hokkaido University, Sapporo, Hokkaido, Japan, Aug 29, 2018 (Invited seminar)


5. Intellectual Property Rights and Other Specific Achievements

Nothing to report.


6. Meetings and Events

Nothing to report.