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

Abstract

<b>Rationale:</b> 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. <b>Methods:</b> In order to evaluate the role of PDK1 in Treg cells from a genetic perspective, mice carrying the floxed <i>PDK1</i> allele were crossbred with <i>Foxp3</i>^Cre mice to efficiently deleted <i>PDK1</i> in Foxp3⁺ Treg cells. Flow cytometry was used to detect the immune cell homeostasis of WT and <i>PDK1^fl/flFoxp3^Cre</i> 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. <b>Results:</b> 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. <b>Conclusion:</b> Our results defined a key finding on the mechanism by which PDK1 regulates Treg cell survival via controlling redox homeostasis.