Author ORCID Identifier

0000-0003-0091-1501

Date of Award

Fall 9-15-2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

First Advisor

Ming-Hui Zou

Second Advisor

Ping Song

Third Advisor

Andrew Gewirtz

Fourth Advisor

Leszek Ignatowicz

Abstract

Regulatory T cells (Tregs) are an essential subtype of immune cells that controls self-tolerance, inflammatory responses, and tissue homeostasis. In tumor immunity, Treg cells are involved in tumor development and progression by inhibiting antitumor immunity. Therapeutically targeting Treg cells in inflammation-related diseases and cancers will therefore require the identification of context-specific mechanisms that guide their functions. The AMP-activated protein kinase (AMPK) functions as a master sensor and modulator of cellular energy and redox homeostasis, both of which are vital to various immune cells including Tregs. However, whether and how AMPK plays its roles in Tregs was unknown. My dissertation aims to elucidate the contributions of AMPK in the regulation of Tregs function in different mouse disease status.

In the first part of this dissertation, I established the essential roles of AMPK in the regulation of immune homeostasis from AMPKα1 global knock-out mice. By using both bone marrow transplantation and the adoptive Treg transfer experiment, I discovered that both Treg dysfunction and the autoimmune diseases occurred in AMPKα1 global knock-out mice. By using Treg-specific AMPKα1 knock-out mice, I further uncovered the indispensable roles of AMPK in the regulation of Treg functions, as the Treg-specific AMPKα1 knock-out mice develops autoimmune disease in livers. Mechanistically, I found that AMPK regulates normal functions of Treg by maintaining the protein stability of Foxp3, a critical transcriptional factor of Tregs.

In the second part, I studied the roles of AMPK in Tregs in tumor growth and metastasis. Treg-specific AMPKα1 knock-out mice exhibited delayed tumor progression and enhanced antitumor T cell immunity. Further experiments showed that AMPKα1 maintains the functional integrity of Treg cells and prevents interferon-γ production in tumor-infiltrating Tregs cells, indicating that AMPK promotes tumor growth by maintaining high levels of Foxp3 in infiltrating Tregs in tumor tissues. Mechanistically, AMPKα1 maintains the protein stability of FOXP3 in Tregs cells by downregulating the expression of E3 ligase CHIP (STUB1). Our results suggest that selective inhibition of AMPK in Tregs cells might be an effective anti-tumor therapy.

In the third part of the dissertation, I interrogated the role of AMPK in Tregs senescence and aging, as a decline of AMPK has been widely described in aged animals and humans. Compared to non-senescent Tregs, senescent Tregs showed fewer protective effects on arterial inflammation and atherosclerosis development. Treg-specific AMPKα1 knock-out mice displayed accelerated Treg senescence and arterial inflammation. Hypercholesterolemia, an established risk factor of cardiovascular diseases, promoted Treg senescence, resulting in the formation of plasticity Tregs with uncontrolled production of interferon-γ and impaired suppressive function. Selective activation of AMPK in Tregs restrained Treg senescence, downregulated the levels of reactive oxygen species (ROS) in aortic walls, and suppressed high fat diets-induced atherosclerosis in mice in vivo. Taken together, my results demonstrates that AMPK activation in Tregs might be a valid target for treating aging related diseases including atherosclerosis.

In conclusion, in this dissertation I have established essential roles of AMPK in maintaining Tregs functions and deregulated AMPK with consequent Tregs dysfunctions plays causative roles in the initiations and progressions of autoimmune liver diseases, cancer, and atherosclerosis-related cardiovascular diseases.

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