Role of Tfh and Tfr in autoimmunity

• Project/Area Number: 15K19129
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Immunology
• Research Institution: Osaka University
• Principal Investigator: Wing James 大阪大学, 免疫学フロンティア研究センター, 特任助教(常勤) (00648694)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: Regulatory T-cells / Humoral Immunity / Regualtory T-cells / T-follicular helper / B-cell responses / 制御性T細胞 / 免疫制御

Outline of Final Research Achievements

T-follicular regulatory T-cells (Tfr) have a critical role for controlling antibody responses by germinal center B-cells. I have discovered that Tfr can differentiate into a mature germinal center resident subset characterised by a lack of expression of the high affinity IL-2 receptor, CD25. This allows the cells to upregulate the IL-2 inhibited transcription factor BCL-6 and travel to the germinal center to suppress B-cells. These cells can be found in both mice and humans and unlike most regulatory T-cells (Tregs), of which Tfr are a subgroup, are inhibited by the presence of IL-2. This demonstrates a fundamental split in regulatory T-cells into IL-2 dependent Tregs and IL-2 independent Tfr and has important implications for many clinical trials using IL-2 to control Treg function.

Research Products

• [Journal Article] T Regulatory Cells Support Plasma Cell Populations in the Bone Marrow. (2017)
  • Author(s): Glatman Zaretsky A, Konradt C, Depis F, Wing JB, Goenka R, Atria DG, Silver JS, Cho S, Wolf AI, Quinn WJ, Engiles JB, Brown DC, Beiting D, Erikson J, Allman D, Cancro MP, Sakaguchi S, Lu LF, Benoist CO, Hunter CA.
  • Journal Title: Cell Reports Volume: 18 Issue: 8 Pages: 906-916
  • DOI: 10.1016/j.celrep.2017.01.067
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The Proportion of Regulatory T Cells in Patients with Rheumatoid Arthritis: A Meta-Analysis. (2016)
  • Author(s): Morita T, Shima Y, Wing JB, Sakaguchi S, Ogata A, Kumanogoh A
  • Journal Title: PLOS one Volume: 11 Issue: 9 Pages: e0162306-e0162306
  • DOI: 10.1371/journal.pone.0162306
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dendritic Cell-Secreted Cytotoxic T-Lymphocyte-Associated Protein-4 Regulates the T-cell Response by Downmodulating Bystander Surface B7. (2016)
  • Author(s): Halpert MM, Konduri V, Liang D, Chen Y, Wing JB, Paust S, Levitt JM, Decker WK
  • Journal Title: Stem Cells Dev Volume: 25 Issue: 10 Pages: 774-87
  • DOI: 10.1089/scd.2016.0009
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] MUCOSAL IMMUNOLOGY. The microbiota regulates type 2 immunity through RORγt+ T cells. (2015)
  • Author(s): Ohnmacht C, Park JH, Cording S, Wing JB, Atarashi K, Obata Y, Gaboriau-Routhiau V, Marques R, Dulauroy S, Fedoseeva M, Busslinger M, Cerf-Bensussan N, Boneca IG, Voehringer D, Hase K, Honda K, Sakaguchi S, Eberl G.
  • Journal Title: Science Volume: 349 Issue: 6251 Pages: 989-993
  • DOI: 10.1126/science.aac4263
  • Peer Reviewed / Int'l Joint Research
• [Presentation] A distinct subset of CD25 negative T-follicular regulatory cells localize in the germinal centers (2016)
  • Author(s): Wing JB.
  • Organizer: 2016 annual meeting of the Japanese Society for Immunology
  • Place of Presentation: Okinawa convention center, Okinawa, Japan
  • Year and Date: 2016-12-05
  • Int'l Joint Research
• [Presentation] A Germinal Center Resident Subset of T-Follicular Regulatory Cells (2016)
  • Author(s): Wing JB.
  • Organizer: Keystone symposium: T Follicular Helper Cells and Germinal Centers (B4)
  • Place of Presentation: Hyatt Regency Monterey, Monterey, California, USA
  • Year and Date: 2016-02-26
• [Presentation] T-Follicular Regulatory Cells (2015)
  • Author(s): Wing JB.
  • Organizer: Invited lecture at National cancer institute
  • Place of Presentation: National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan
  • Year and Date: 2015-11-24
  • Invited
• [Book] Chronic inflammation: Devising Novel Methods to Control Chronic Inflammation Via Regulatory T Cells (2016)
  • Author(s): James B. Wing, Atsushi Tanaka, Shimon Sakaguchi
  • Total Pages: 13
  • Publisher: Springer
• [Book] Progress in Molecular Biology and Translational Science. Chapter 1- Transcriptional and Epigenetic Control of Regulatory T Cell Development. (2015)
  • Author(s): Kitagawa Y, Wing JB, Sakaguchi S.
  • Total Pages: 33
  • Publisher: Elsevier