The role of novel TCR-PKD-SHP-1 axis in CD4+ T cell development
| Project/Area Number |
16K08841
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Immunology
|
|---|
| Research Institution | Osaka University |
|---|
Principal Investigator |
Ishikawa Eri 大阪大学, 微生物病研究所, 助教 (20546478)
|
|---|
| Project Period (FY) |
2016-04-01 – 2019-03-31
|
| Project Status |
Completed (Fiscal Year 2018)
|
| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
|
|---|
| Keywords | T細胞分化 / セリンスレオニンキナーゼ / チロシンフォスファターゼ / 免疫シグナル伝達 |
|---|
| Outline of Final Research Achievements |
We previously demonstrated that serine/threonine kinase, protein kinase D (PKD) plays a crucial role in CD4+ T cell development by generating T cell-specific PKD deficient mice and found tyrosine phosphatase SHP-1 as a substrate of PKD in thymocytes. We generated phosphorylation-defective mutant SHP-1 knock-in mice (KI) to reveal the contribution of TCR-PKD-SHP-1 axis in CD4+ T cell development. Indeed, phosphorylation of SHP-1 was not observed in thymocytes from KI mice. In competitive bone marrow (BM) chimera mice of WT and KI BM, generation of CD4+ T cells from KI cells was impaired, indicating that phosphorylation of SHP-1 by PKD is critical for CD4+ T cell development. Phosphatase activity and localization of SHP-1 was not affected by the mutation. We also analyzed PKD and SHP-1 multiple knockout mice and revealed that impaired TCR signaling by PKD deficiency was slightly restored in these mice, suggesting that PKD regulates the function of SHP-1 through unknown mechanisms.
|
| Academic Significance and Societal Importance of the Research Achievements |
T細胞は胸腺でTCRによりMHC－自己抗原ペプチド複合体を認識することで様々な選択を受けて分化するが、親和性の違いを細胞運命決定につなげる分子機構は、現在免疫学に残された重要な課題の１つである。TCR下流のチロシンキナーゼを介したチロシンリン酸化によるシグナル調節機構はよく知られているが、セリン/スレオニンリン酸化の役割に関しては未だ不明な点が多い。本研究で得られた結果は、T細胞分化においてTCR-PKD-SHP-1 axis が存在し、TCR下流でセリン/スレオニンキナーゼがチロシンフォスファターゼを制御するという新たな経路の重要性を強く示唆するものである。
|
Report
(4 results)
Research Products
(8 results)
-
-
[Journal Article] Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1.2016
Author(s)
Ishikawa, E., Kosako, H., Yasuda, T., Ohmuraya, M., Araki, K., Kurosaki, T., Saito, T. and Yamasaki, S.
-
Journal Title
Nat. Commun.
Volume: 7
Pages: 12756-12756
DOI
NAID
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
-
-
-
-
-
-
