2015 Fiscal Year Research-status Report
Role of Tfh and Tfr in autoimmunity
| Project/Area Number |
15K19129
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| Research Institution | Osaka University |
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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)
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| Project Period (FY) |
2015-04-01 – 2017-03-31
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| Keywords | 制御性T細胞 / 免疫制御 |
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| Outline of Annual Research Achievements |
How antibody responses are regulated is a critical question in the understanding of autoimmunity and responses to infection. The T-dependent antibody response is controlled to a large extent by T-follicular helper (Tfh) cells which can travel to the B-cell follicle and germinal centers. However, the exact role of Tfh in a number of autoimmune diseases remains to be determined. Correspondingly regulatory T-cells have a specialized subset, T-follicular regulatory cells (Tfr), that may act to suppress Tfh function. While early results suggest that Tfr do control Tfh much is still unknown about the function and phenotype of Tfr.
I have made several key findings in the last year. It has previously been demonstrated that unrestrained antibody production and in particular very high levels of IgE follow loss of Treg function. Using the BCL6 flox mouse I have found that Tfh cells are responsible for almost all of this antibody production seen in either mice lacking Foxp3 function (scurfy mice) or mice where Tregs are specifically ablated. Early data using PD-1 flox suggests that Tfr may gain function in the absence of PD-1. Further to this, as described below, in the course of this work I have made a significant discovery concerning Tfr located in the germinal centers.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
While carrying out the planned research I have made a significant discovery regarding the phenotype of Tfr cells. I have found that Tfr have a subgroup of Foxp3 positive but CD25 negative cells with increased expression of Tfh associated markers such as CXCR5, PD1 and BCL6. However the CD25-Tfr retain their suppressive function. I have confirmed that these CD25 negative Tfr are preferentially localized in the germinal centers and have named them GC-Tfr. Due to their localization are likely to be more critical to the control of autoimmunity that other Tfr in a similar manner to GC-Tfh which are a highly functional subset of Tfh located in germinal centers. This is an important finding that may help to clarify the role of Tfr in various diseases. As a result this work can now focus on Tfh, Tfr and the newly discovered GC-Tfr in autoimmunity.
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| Strategy for Future Research Activity |
In the next year I will continue the proposed research with some modifications to accommodate the new discovery of GC-Tfr. I will continue to use the BCL6 flox mice and have recently crossbred them with CTLA-4 flox to examine the effect of loss of Tfh function in the context of loss of Treg suppressive mechanisms such as CTLA-4. In addition I will continue to characterize GC-Tfr. In vivo antibody blocking (anti-PD1 and anti-CTLA-4) will also be used to assess the effect on Tfh, Tfr and GC-Tfr.
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| Causes of Carryover |
In the next year costs will be higher as several expensive reagents must be bought, in particular large quantities of antibodies for in vivo use (anti-CTLA4, anti-PD1). Originally this was planned for FY2017 but was delayed due to the need to investigate GC-Tfr.
Additionally travel expenses are slightly higher than originally planned as I will attend both a Keystone symposium and the Japanese society for Immunology meeting in Okinawa.
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| Expenditure Plan for Carryover Budget |
物品費 Article Costs 1,687,923 旅費 Travel Expenses 350,000, 人件費・謝金 Personnel Expenditure and Remuneration 0, その他 Miscellaneous 100,000, 計(c) Total 2,137,923
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Research Products
(4 results)
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[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.
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Journal Title
Science
Volume: 349
Pages: 989-993
DOI
Peer Reviewed / Int'l Joint Research
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[Presentation] T-Follicular Regulatory Cells2015
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 – 2015-11-24
Invited
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