Analysis of PI3K signaling role in regulatory B cells

• Project/Area Number: 23791260
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Dermatology
• Research Institution: Kanazawa University
• Principal Investigator: MATSUSHITA Takashi 金沢大学, 医学系, 医学系 (60432126)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 制御性B細胞 IL-10 / 自己免疫疾患 / 制御性B細胞 / IL-10

Research Abstract

IL-10 producing regulatory B (Breg) cells negatively regulates autoimmune disease and inflammation, such as contact hypersensitivity (CHS). CD19 expression is critical for Breg cells development, since CD19 loss results in decreased number of Breg cell and increased reactivity of CHS. However, molecular mechanism of Breg cell development remains poorly understood. CD19 downstream signal is depend on the activation of phosphoinositide 3-kinases (PI3K)-AKT pathways, while phosphatase and tensin homologue (PTEN) attenuates PI3K-AKT pathways. In this study, we investigated the role of PI3K-AKT pathway in the development of Breg cells. The effect of PI3K-AKT pathway inhibitors on Breg cell development was examined in vitro. B cell-specific PTEN deficient mice, which exhibit aberrant activation of PI3K-AKT pathway in B cell, were generated using Cre-loxp system. CHS severity in B cell-specific PTEN deficient mice was investigated. The current studies demonstrate that PI3K-AKT pathway inhibitors reduced Breg cells in vitro in dose-dependent manner. However, PTEN inhibitor had no effect on Breg cells. Breg cell number and frequency were significantly increased in various organs of B cell-specific PTEN deficient mice when compared with wild-type mice. Furthermore, CHS response was significantly diminished in B cell-specific PTEN deficient mice when compared with wild-type mice. Thus, PI3K-AKTpathway positively regulates Breg cell development, while PTEN negatively regulates it. PI3K-AKT pathway in B cell is critical for Breg cell development and could be a potent therapeutical target.

Research Products

• [Journal Article] Donor-derived regulatory B cells are important for suppression of murine sclerodermatous chronic graft-versus-host disease (2013)
  • Author(s): Le Huu D, Matsushita T, Jin G, Hamaguchi Y, Hasegawa M, T akehara K, T edder TF, Fujimoto M
  • Journal Title: Blood Volume: 121 Issue: 16 Pages: 3274-83
  • DOI: 10.1182/blood-2012-11-465658
  • Peer Reviewed
• [Journal Article] BLNK expression contributes to controlling allergic and autoimmune diseases by mediating IL-10 production in regulatory B cells (2013)
  • Author(s): Jin G, Hamaguchi Y, Matsushita T, Hasegawa M, Huu DL, Ishiura N, Naka K, Hirao A, Takehara K, Fujimoto M
  • Journal Title: J Allergy Clin Immunol Volume: 131 Issue: 6 Pages: 1674-1682
  • DOI: 10.1016/j.jaci.2013.01.044
  • Peer Reviewed
• [Journal Article] Autoantibodies to small ubiquitin-like modifier activating enzymes in Japanese patients with dermatomyositis: comparison with a UK Caucasian cohort. (2013)
  • Author(s): Fujimoto M
  • Journal Title: Ann Rheum Dis Volume: 72 Issue: 1 Pages: 151-153
  • DOI: 10.1136/annrheumdis-2012-201736
  • Peer Reviewed
• [Journal Article] Donor-derived regulatory B cells are important for suppression of murine sclerodermatous chronic graft-versus-host disease. (2013)
  • Author(s): Le Huu D, Matsushita T, Jin G, Hamaguchi Y, Hasegawa M, Takehara K, Tedder TF, Fujimoto M.
  • Journal Title: Blood Volume: in press
  • Peer Reviewed
• [Journal Article] Autoantibodies to small ubiquitin-like modifier activating enzymes in Japanese patients with dermatomyositis: comparison with a UK Caucasian cohort. (2013)
  • Author(s): Fujimoto M, Matsushita T, Hamaguchi Y, Kaji K, Asano Y, Ogawa F, Yamaoka T, Fujikawa K, Tsukada T, Sato K, Echigo T, Hasegawa M, Takehara K.
  • Journal Title: Ann Rheum Dis. Volume: 72 Pages: 151-153
  • Peer Reviewed
• [Journal Article] B-cell linker protein expression contributes to controlling allergic and autoimmune diseases by mediating IL-10 production in regulatory B cells. (2013)
  • Author(s): Jin G, Hamaguchi Y, Matsushita T, Hasegawa M, Le Huu D, Ishiura N, Naka K, Hirao A, Takehara K, Fujimoto M.
  • Journal Title: J Allergy Clin Immunol. Volume: in press
  • Peer Reviewed
• [Journal Article] Anti-NXP2 autoantibodies in adult patients with idiopathic inflammatory myopathies : possible association with malignancy (2012)
  • Author(s): Ichimura Y, Matsushita T, Hamaguchi Y, Kaji K, Hasegawa M, Tanino Y, Inokoshi Y, Kawai K, Kanekura T, Habuchi M, Igarashi A, Sogame R, Hashimoto T, Koga T, Nishino A, Ishiguro N, Sugimoto N, Aoki R, Ando N, Abe T, Kanda T, Kuwana M, Takehara K, Fujimoto M
  • Journal Title: Ann Rheum Dis Volume: 71(5) Issue: 5 Pages: 710-3
  • DOI: 10.1136/annrheumdis-2011-200697
  • NAID: 120004442395
  • Peer Reviewed
• [Journal Article] Potential roles of interleukin 17A in the development of skin fibrosis. (2012)
  • Author(s): Okamoto Y, Hasegawa M, Matsushita T, Hamaguchi Y, Huu DL, Iwakura Y, Fujimoto M, Takehara K.
  • Journal Title: Arthritis Rheum. Volume: 64 Pages: 3726-3735
  • Peer Reviewed
• [Journal Article] Anti-NXP2 autoantibodies in adult patients with idiopathic inflammatory myopathies: possible association with malignancy. (2012)
  • Author(s): Ichimura Y
  • Journal Title: Ann Rheum Dis. Volume: 71 Pages: 710-713
  • Peer Reviewed
• [Journal Article] haracterization of a Rare IL-10-Competent B Cell Subset in Man That Parallels Mouse Regulatory B10 Cells (2011)
  • Author(s): Iwata Y*, Matsushita T*, Horikawa, DiLillo, Yanaba, Venturi, Szabolcs, Bernstein, Magro, Williams, Hall, St.Clair, and Tedder TF
  • Journal Title: Blood Volume: 117 Issue: 2 Pages: 530-41
  • DOI: 10.1182/blood-2010-07-294249
• [Journal Article] Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice (2011)
  • Author(s): Horikawa M, Minard-Colin V, Matsushita T, Tedder TF
  • Journal Title: J Clin Invest Volume: 121 Issue: 11 Pages: 4268-4280
  • DOI: 10.1172/jci59266
• [Journal Article] Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice. (2011)
  • Author(s): HOrikawa M
  • Journal Title: J Clin Invest. Volume: 121 Pages: 4268-4280
  • Peer Reviewed
• [Presentation] PI3K-Akt pathway modulates IL-10 producing regulatory B cell (2012)
  • Author(s): Matsushita T, Le Huu D, Fujimoto M, Takehara K
  • Organizer: The 37th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: Okinawa, LOISIR HOTEL & SPA TOWER NAHA
  • Year and Date: 2012-12-07
• [Presentation] PI3K-Akt pathway modulates IL-10 producing regulatory B cell. (2012)
  • Author(s): Matsushita T
  • Organizer: The 37th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 沖縄、ロワジールホテル＆スパタワー那覇