Regulatory roles of HIF-1a and glycolysis in autoimmunity

• Project/Area Number: 24591454
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Dokkyo Medical University
• Principal Investigator: KOBATA Tetsuji 獨協医科大学, 医学部, 教授 (10205445)
• Co-Investigator(Renkei-kenkyūsha): HASHIGUCHI Masaaki 獨協医科大学, 医学部, 准教授 (20372443) ; KASHIWAKURA Yuji 獨協医科大学, 医学部, 助教 (40382890)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 自己免疫 / HIF-1a / 解糖系 / B細胞分化 / HIF-1α / 制御性T細胞

Outline of Final Research Achievements

In order to understand the pathophysiology of HIF-1α/RAG-2–deficient chimeric mice, which develop autoimmunity resembling human systemic erythematosus, we analyzed mice with conditional knock-outs in HIF-1α in B cells and revealed that autoantibody production is regulated by HIF-1α in the very early stages of B cell development and/or HIF-1α in cells other than B cells. Although HIF-1α/RAG-2–deficient chimeric mice have increased regulatory T cells, we found that regulatory T cells less depend on glycolysis and need CD2-mediated down-regulation of pro-apoptotic Bim for their survival.

Research Products

• [Journal Article] CD2-mediated regulation of peripheral CD4+CD25+ regulatory T cell apoptosis accompanied with down regulation of Bim (2013)
  • Author(s): Kashiwakura Y, Sakurai D, Kanno Y, Hashiguchi M, Kobayashi A, Kurosu A, Tokudome S, Kobata T, Kojima H.
  • Journal Title: Immunology Volume: 139 Issue: 1 Pages: 48-60
  • DOI: 10.1111/imm.12054
  • Peer Reviewed
• [Presentation] CD2 stimulation upregulates Foxp3 in murine peripheral regulatory T cells (2014)
  • Author(s): Kashiwakura Y, Kanno Y, Hashiguchi M, Kobata T, Kojima H
  • Organizer: 第４3回日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-12
• [Presentation] Cellular metabolism of CD4+ CD25+ regulatory T cells is distinct from that of CD4+ CD25- conventional T cells (2014)
  • Author(s): Kojima H, Kanno Y, Kashiwakura Y, Hashiguchi M, Kobata T
  • Organizer: 第４3回日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-12
• [Presentation] Glycolysis, that impacts on bone marrow B cell development, dose not have a decisive influence on peripheral B cell differentiation (2014)
  • Author(s): Kanno Y, Kashiwakura T, Hashiguchi M, Kobata T, Kojima H
  • Organizer: 第４3回日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-11
• [Presentation] TCR-independent CD4+CD25+ regulatory T cell activation during immune responses (2013)
  • Author(s): Kojima H, Kashiwakura Y, Hashiguchi M, Kobata T.
  • Organizer: 15th international Congress of Immunology
  • Place of Presentation: Milan, Italy
• [Presentation] CD2-mediated regulation of peripheral CD4+CD25+ regulatory T cell apoptosis accompanied by downregulation of Bim (2013)
  • Author(s): Kashiwakura Y, Sakurai D, Kanno Y, Hashiguchi M, Kobayashi A, Kurosu A, Tokudome S, Kobata T, Kojima H.
  • Organizer: 15th international Congress of Immunology
  • Place of Presentation: Milan, Italy
• [Presentation] HIF-1α is regulated by IL-7 in pro-B cells during B cell development. (2013)
  • Author(s): Kanno Y, Kashiwakura T, Hashiguchi M, Kobata T, Kojima H.
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 千葉市
• [Presentation] Cytokine-dependent CD4+CD25+ regulatory T cell activation during immune responses (2013)
  • Author(s): Kojima H, Kanno Y, Kashiwakura Y, Hashiguchi M, Kobata T.
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 千葉市
• [Presentation] CD2-mediated regulation of peripheral CD4+CD25+ regulatory T cell apoptosis accompanied by down regulation of Bim (2013)
  • Author(s): Kashiwakura Y, Sakurai D., Kanno Y, Hashiguchi M, Kobata T, Kojima H.
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 千葉市
• [Presentation] Peripheral CD4+ CD25+ regulatory T cell survival is regulated by a combination of CD2 stimuli and the interaction with stromal cells
  • Author(s): Kashiwakura Y, Kanno Y, Hashiguchi M, Kobata T, Kojima H.
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
• [Presentation] Characterization of activated CD4+ CD25+ regulatory T cells during immune responses
  • Author(s): Kojima H, Kanno Y, Kashiwakura Y, Hashiguchi M, Kobata T.
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
• [Presentation] IL-7 is a principal factor for HIF-1α regulated pro-B development
  • Author(s): Kanno Y, Kashiwakura T, Hashiguchi M, Kobata T, Kojima H.
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）