| 研究課題/領域番号 |
25860356
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| 研究種目 |
若手研究(B)
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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 (00648694)
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| 研究期間 (年度) |
2013-04-01 – 2015-03-31
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| キーワード | 制御性T細胞 / 免疫制御 |
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| 研究概要 |
Understanding how antibody production is regulated is critical to both developing improved vaccines to infectious diseases, such as Influenza and HIV, the control of antibody dependent auto-immune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, and control of allergic responses. The purpose of this research is to further investigate and understand both the importance and mechanisms used by regulatory T-cells (Tregs) in the control of antibody responses. To do this we use a combination of conditional knockout mice, in which genes are specifically deleted in cell populations of interest and Treg cell deletion to study their effects in the context of vaccination.
We have made a number of research achievements in the last year. We have been able to demonstrate that when Tregs are deleted large numbers of antigen specific T-follicular helper cells, critical for delivery of help to B-cells are formed. Correspondingly antigen specific B-cells are enhanced and produce increased levels of antibody both following primary vaccination but also in memory vaccination. This suggests that depletion of Tregs is both able to enhance vaccine responses immediately but also, importantly, enhances long lasting immunity even after Treg levels have recovered. This is critical as it allows Treg depletion to enhance vaccine responses while not compromising their role in protection from autoimmunity. Furthermore as outlined below we have made significant progress in enhancing our understand of the mechanisms by which Tregs inhibit antibody production.
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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
A critical part of this project is to further our understanding of the mechanisms by which Tregs and their more specific antibody regulating subset T-follicular regulatory cells control humoral immunity. We have made significant progress into this goal. The Treg suppressive molecule CTLA-4 acts primarily by depleting the co-stimulatory molecules CD80 and 86 from antigen presenting cells. We have found that B-cell expression of CD80 and CD86 is sufficient to induce T-follicular helper cell formation and that depletion of Tregs enhances expression of these molecules by B-cells. Use of anti-CTLA-4 blocking antibodies has allowed us to demonstrate that antigen specific T-follicular helper cells (the cells critical for delivery of help to antibody producing B-cells) are significantly upregulated following anti-CTLA-4 treatment allowing greatly increased antibody production. Further, using Treg cell targeted deletion of the CTLA-4 gene, we have demonstrated that Treg cell specific CTLA-4 is critical to this process. Interestingly in these mice numbers of both Tregs and T-follicular regulatory cells are also increased demonstrating that in the absence of Treg CTLA-4 expression even large numbers of these cells are unable to prevent antibody production. In particular we have found that the antibody isotype IgE, critical for allergic responses is strongly affected by the loss of Treg CTLA-4 function.
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| 今後の研究の推進方策 |
While we have already made significant progress the research is In FY2014 work will continue to further investigate the Treg subset, T-follicular regulatory cells. BCL6 is a transcription factor essential for the maintenance of both T-follicular regulatory cells and T-follicular helper cells. We have generated BCL6 conditional knockout mice that lack BCL-6 expression in all CD4+ T-cells. We will use this system to specifically address the effect of deletion of T-follicular helper cells on the production of antibodies both with and without Treg depletion. We have also obtained several cytokine reporter mice that will allow us to specifically assess production cytokines critical to Tfh function such as IL-21 and IL-4 in following Treg depletion and CTLA-4 blocking experiments. Further we will use combinations of BCL6 cKO, CTLA-4 cKO and CTLA-4 antibody blocking to more clearly demonstrate the role of CTLA-4 on T-follicular regulatory cells in particular.
While I am confident that I will be able to answer the questions that I have set out to investigate, if the research does not progress according to plan we have several back up options. For example we could further investigate the role of other Treg suppressive molecules such as IL-10 and PD-1.
Post FY2014 we intend to continue this line of research using the systems developed during this study to carry out further detailed studies into the function of Tregs/Tfregs/Tfh in models of autoimmunity and allergy.
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| 次年度の研究費の使用計画 |
We anticipate spending more in FY2014 since the systems developed in FY2013 will allow us to accelerate our research incurring higher consumable costs. In addition since the project is in a more advanced stage travel costs to present results are likely to be higher.
Original plan FY2014 物品費 1,175,000 旅費 275,000 その他 50000 合計 1500000 円 FY2013 underspend 349582 円
Revised plan FY2014 物品費 1,524,582 旅費 275,000 その他 50000 合計 1849582 円
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