Roles of BCL-3 in the development of TFH cells and the pathogenesis of rheumatoid arthritis

• Project/Area Number: 26461460
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Chiba University
• Principal Investigator: SUZUKI Kotaro 千葉大学, 医学部附属病院, 講師 (90554634)
• Co-Investigator(Kenkyū-buntansha): 池田 啓 千葉大学, 医学部附属病院, 助教 (10456014) ; 廣瀬 晃一 千葉大学, 大学院医学研究院, 准教授 (90400887)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 関節リウマチ / Bcl-3 / Bcl-6 / 濾胞ヘルパーT細胞 / BCL-3 / BCL-6 / CD4陽性T細胞 / Tfh細胞 / BCL－３

Outline of Final Research Achievements

We have previously shown that expression of the Bcl-3 gene is down-regulated in CD4+ T cells from patients with rheumatoid arthritis (RA) following tocilizumab therapy. The objective of this study was to examine the role of Bcl-3 in the pathogenesis of RA. We examined the roles of IL-6 signaling in the induction of Bcl-3. We analyzed the gene expression profiles of Bcl-3-transduced CD4+ T cells by RNA sequencing. The effects of enforced expression of Bcl-3 on the development of follicular helper T (Tfh) cells were evaluated. IL-6 induced Bcl-3 expression in CD4+ T cells in a STAT3-dependent manner. Transcriptome analysis revealed that the expression of Bcl-6, a master regulator of Tfh cell differentiation, was significantly up-regulated by the enforced Bcl-3 expression. The enforced Bcl-3 expression increased the numbers of IL-21-producing Tfh-like cells. Bcl-3 is involved in the development of Tfh cells and the pathogenesis of RA, presumably by inducing IL-21 production.

Research Products

• [Journal Article] IκBNS induces Muc5ac expression in epithelial cells and causes airway hyperresponsiveness in murine asthma models (2017)
  • Author(s): Yokota M, Tamachi T, Yokoyama Y, Maezawa Y, Takatori T, Suto A, Suzuki K, Hirose K, Takeda K, Nakajima H
  • Journal Title: Allergy Volume: 印刷中 Issue: 7 Pages: 13079-13079
  • DOI: 10.1111/all.13079
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] T-bet inhibits innate lymphoid cell-mediated eosinophilic airway inflammation by suppressing IL-9 production (2017)
  • Author(s): Matsuki A, Takatori T, Makita S, Yokota M, Tamachi T, Suto A, Suzuki K, Hirose K, Nakajima H
  • Journal Title: J. Allergy Clin. Immunol Volume: 印刷中 Issue: 4 Pages: 31023-31025
  • DOI: 10.1016/j.jaci.2016.08.022
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] IkBNS enhances follicular helper T-cell differentiation and function downstream of ASCL2. (2016)
  • Author(s): Hosokawa J, Suzuki K, Meguro K, Tanaka S, Maezawa Y, Suto A, Fujimura L, Sakamoto A, Clevers H, Ohara O, Nakajima H.
  • Journal Title: J Allergy Clin Immunol. Volume: S0091-6749 Issue: 1 Pages: 32476-32479
  • DOI: 10.1016/j.jaci.2016.10.047
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] SOCS3 expressed in M2 macrophages attenuates contact hypersensitivity by suppressing MMP12 production (2016)
  • Author(s): Meguro K, Nakagomi D, Suzuki K, Hosokawa J, Fukuta T, Yokota M, Maezawa Y, Suto A, Nakajima H
  • Journal Title: J Invest Dermatol Volume: in press Issue: 3 Pages: 649-57
  • DOI: 10.1016/j.jid.2015.12.010
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MMP12 is produced by M2 monocytes-macrophages and plays important roles in the development of contact hypersensitivity (2015)
  • Author(s): Nakagomi D, Suzuki K, Meguro K, Hosokawa J, Tamachi T, Takatori H, Suto A, Matsue H, Ohara O, Nakayama T, Shimada S, Nakajima H
  • Journal Title: J Allergy Clin Immunol Volume: 135 Issue: 5 Pages: 1397-400
  • DOI: 10.1016/j.jaci.2014.10.055
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Roles of B Cell Leukemia/Lymphoma 3 in the development of T follicular helper cells and the pathogenesis of rheumatoid arthritis. (2015)
  • Author(s): Meguro, K., Suzuki, K., Hosokawa, J., Sanayama, Y., Tanaka, S., Furuta, S., Ikeda, K., Takatori, H, Suto, A., Sakamoto, A., Ohara, O., Nakajima, H.
  • Journal Title: Arthritis & Rheumatology Volume: 67 Issue: 10 Pages: 2651-60
  • DOI: 10.1002/art.39266
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukemic transformation. (2014)
  • Author(s): Sashida, G., Harada, H., Matsui, H., Oshima, M., Yui, M., Harada, Y., Tanaka, S., Mochizuki-Kashio, M., Wang, C., Saraya, A., Muto, T., Hayasi, Y., Suzuki, K., Nakajima, H., Inaba, T., Koseki, H., Huang, G., Kitamura, T. and Iwama, A.
  • Journal Title: Nat. Commun. Volume: 5 Issue: 1 Pages: 5177-5177
  • DOI: 10.1038/ncomms5177
  • Peer Reviewed / Open Access
• [Journal Article] Sox5 and c-Maf cooperatively induce Th17 cell differentiation via ROR gamma t induction as downstream targets of Stat3 (2014)
  • Author(s): Tanaka S, Suto A, Iwamoto T, Kashiwakuma D, Kagami S, Suzuki K, Takatori H, Tamachi T, Hirose K, Onodera A, Suzuki J, Ohara O, Yamashita M, Nakayama T, Nakajima H
  • Journal Title: J Exp Med Volume: 211 Issue: 9 Pages: 1857-1874
  • DOI: 10.1084/jem.20130791
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Roles of B Cell Leukemia/Lymphoma 3 in the Development of T Follicular Helper Cells and the Pathogenesis of Rheumatoid Arthritis (2015)
  • Author(s): MEGURO Kazuyuki, SUZUKI Kotaro, HOSOKAWA Junichi, SUTO Akira, NAKAJIMA Hiroshi
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（札幌 北海道）
  • Year and Date: 2015-11-18
• [Presentation] Roles of B Cell Leukemia/Lymphoma 3 in the Development of T Follicular Helper Cells and the Pathogenesis of Rheumatoid Arthritis. (2015)
  • Author(s): K. Meguro, K. Suzuki, J. Hosokawa, Y. Sanayama, S. Tanaka, S. Furuta, K. Ikeda, H. Takatori, A. Suto, O. Ohara, H. Nakajima
  • Organizer: Annual Congress of the European League against Rheumatism
  • Place of Presentation: ローマ イタリア
  • Year and Date: 2015-06-10
  • Int'l Joint Research
• [Presentation] Role of tumor suppressor p53 in Tc17 differentiation. (2014)
  • Author(s): Meguro K, Suzuki K, Hosokawa J, Yokota M, Takatori H, Nakajima H.
  • Organizer: 第４３回日本免疫学会総会•学術集会
  • Place of Presentation: 国立京都国際会館 (京都府京都市)
  • Year and Date: 2014-12-12
• [Presentation] Sox5 and c-mad cooperatively induce Th17 cell differentiation via RORgt induction as downstream targets of Stat3. (2014)
  • Author(s): Tanaka S, Suto A, Iwamoto T, Suzuki K, Takatori H, Tamachi T, Hirose K, Onodera A, Suzuki J, Ohara O, Yamashita M, Nakayama T, Nakajima H.
  • Organizer: 第４３回日本免疫学会総会•学術集会
  • Place of Presentation: 国立京都国際会館 (京都府京都市)
  • Year and Date: 2014-12-12