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Theranostics 2021; 11(19):9503-9518. doi:10.7150/thno.63992 This issue Cite

Research Paper

The kinase PDK1 regulates regulatory T cell survival via controlling redox homeostasis

Peiran Feng^1,2#, Quanli Yang^1,2#, Liang Luo^1,2, Yadong Sun^1,2, Wenkai Lv^1,2, Shuo Wan^1,2, Zerong Guan^1,2, Zhiqiang Xiao^1,2, Feng Liu^1,2, Zehua Li³, Zhongjun Dong^3✉, Meixiang Yang^1,2✉

1. Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Jinan University, Zhuhai, Guangdong, 519000, China.
2. The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, 510632, China.
3. School of Medicine and Institute for Immunology, Tsinghua University, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, 100084, China.
#Co-first authors.

✉ Corresponding authors: Dr. Zhongjun Dong, Medical Blvd. D328, Tsinghua University, Haidian District, Beijing, 100086, China; Phone: +86-10-62798536; dongzjtsinghua.edu.cn. Dr. Meixiang Yang, 601 West Huangpu Avenue, Guangzhou, Guangdong, 510632, China; Phone: +86 13422034040; mxyangedu.cn. More

Abstract

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/flFoxp3^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 Fe²⁺ 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.

Keywords: Treg cell, PDK1, ROS, Iron homeostasis, MAPK, Immune cell death

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