| First Author | Feng P | Year | 2021 |
| Journal | Theranostics | Volume | 11 |
| Issue | 19 | Pages | 9503-9518 |
| PubMed ID | 34646383 | Mgi Jnum | J:314118 |
| Mgi Id | MGI:6788521 | Doi | 10.7150/thno.63992 |
| Citation | Feng P, et al. (2021) The kinase PDK1 regulates regulatory T cell survival via controlling redox homeostasis. Theranostics 11(19):9503-9518 |
| abstractText | Rationale: Regulatory T cells (Treg cells) play an important role in maintaining peripheral tolerance by suppressing over-activation of effector T cells. The kinase PDK1 plays a pivotal role in conventional T cell development. However, whether PDK1 signaling affects the homeostasis and function of Treg cells remains elusive. Methods: In order to evaluate the role of PDK1 in Treg cells from a genetic perspective, mice carrying the floxed PDK1 allele were crossbred with Foxp3 (Cre) mice to efficiently deleted PDK1 in Foxp3(+) Treg cells. Flow cytometry was used to detect the immune cell homeostasis of WT and PDK1(fl/fl)Foxp3(Cre) mice. RNA-seq was used to assess the differences in transcriptional expression profile of WT and PDK1-deficient Treg cells. The metabolic profiles of WT and PDK1-deficient Treg cells were tested using the Glycolysis Stress Test and Mito Stress Test Kits by the Seahorse XFe96 Analyser. Results: PDK1 was essential for the establishment and maintenance of Treg cell homeostasis and function. Disruption of PDK1 in Treg cells led to a spontaneous fatal systemic autoimmune disorder and multi-tissue inflammatory damage, accompanied by a reduction in the number and function of Treg cells. The deletion of PDK1 in Treg cells destroyed the iron ion balance through regulating MEK-ERK signaling and CD71 expression, resulting in excessive production of intracellular ROS, which did not depend on the down-regulation of mTORC1 signaling. Inhibition of excessive ROS, activated MEK-Erk signaling or overload Fe(2+) could partially rescue the survival of PDK1-deficient Treg cells. Conclusion: Our results defined a key finding on the mechanism by which PDK1 regulates Treg cell survival via controlling redox homeostasis. |
