Role of Tfh and Tfr in autoimmunity

2016 Fiscal Year Annual Research Report

• Project/Area Number: 15K19129
• Research Institution: Osaka University
• Principal Investigator: ウィング ジェイムス 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
• Keywords: Regualtory T-cells / T-follicular helper / B-cell responses / Humoral Immunity

Outline of Annual Research Achievements

Regulatory T-cells (Tregs) were initially identified by their expression of the IL-2 receptor CD25 and later by the transcription factor Foxp3. A subgroup of Treg, T-follicular regulatory (Tfr) cells are believe to be critical to the control of T-follicular helper cells (Tfh) and resulting germinal centre B-cell antibody responses. However, we do not understand the biology of Tfr cells well. This project set out to better understand the role of Tfr in autoimmunity.
We made the important finding that mature Tfr cells downregulate CD25 expression and form a subgroup of CD25lo Tfr that preferentially locate in the germinal centres. Tfr lose CD25 expression in order to upregulate the Tfh associated transcription factor BCL6 which is otherwise inhibited by IL-2 signalling via CD25. This loss of dependence on IL-2 makes Tfr unique among the otherwise IL-2 dependent group of Tregs. We found that these CD25lo Tfr are present in both mice and also human blood and tonsils. We characterised human Tregs and find that up to 30% are CXCR5+CD25lo Tfr. Despite loss of CD25 Tfr retain expression of Foxp3 and other critical Treg molecules such as CTLA-4. These findings are a significant step towards our understanding of Tfr biology and also have wider implications since many treatments currently investigated in human clinical trials rely on either manipulation of IL-2 availability or depletion of Tregs via anti-CD25 antibodies.The resulting paper is currently under review.

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 Pages: 906-916
  • DOI: 10.1016/j.celrep.2017.01.067
  • Peer Reviewed / 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 Pages: -
  • 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 Pages: 774-87
  • DOI: 10.1089/scd.2016.0009
  • 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 – 2016-12-07
  • Int'l Joint Research
• [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