| 研究課題/領域番号 |
15K19129
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| 研究機関 | 大阪大学 |
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研究代表者 |
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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| 研究期間 (年度) |
2015-04-01 – 2017-03-31
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| キーワード | 制御性T細胞 / 免疫制御 |
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| 研究実績の概要 |
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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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
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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| 今後の研究の推進方策 |
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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| 次年度使用額が生じた理由 |
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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| 次年度使用額の使用計画 |
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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