The role of cholesterol metabolism and estrogen signaling in regulating visceral adipose tissue regulatory T cell accumulation, phenotype and function Restricted; Files Only

Abstract

A population of regulatory T cells (Tregs) in the visceral adipose tissue (VAT) is critical for controlling VAT inflammation and promoting metabolic health. VAT Tregs exhibit an activated/effector phenotype and a clonally expanded T cell receptor (TCR) repertoire. In addition to their core Foxp3-dependent suppressive program, VAT Tregs also express a unique transcriptional signature dependent on the transcription factor PPARγ, the master regulator of adipocyte differentiation and lipid storage. While VAT Tregs are highly enriched at steady state, they are lost in multiple models of obesity, which exacerbates VAT inflammation and promotes metabolic disease. Recent studies highlight the presence of distinct VAT Treg subsets including ST2+ Th2-like VAT Tregs and CXCR3+ Th1-like VAT Tregs which vary in their relative abundance across sex and dietary conditions. However, whether obesity disrupts VAT Treg metabolism to drive the loss of specific VAT Treg subsets remains unknown. Additionally, while sex hormones such as estrogen have been shown to regulate the phenotype and abundance VAT Tregs at steady state, their impact on the VAT Treg subset composition and function during obesity has not been explored. 

The work in this thesis provides two main contributions to the field of VAT Treg biology. First, utilizing unique TCR-transgenic (vTreg53) and conditional knockout mouse models along with CRISPR/Cas9, flow cytometry, single-cell omics, and metabolic assays, this work identifies a critical role for SREBP2-mediated cholesterol biosynthesis in supporting the accumulation of ST2hi VAT Treg subsets. Mechanistically, cholesterol was important for potentiating strong TCR signaling to promote the preferential clonal expansion of ST2hi VAT Treg subsets. However, obesity disrupted VAT Treg cholesterol metabolism, leading to a preferential loss of insulin-sensitizing ST2hi VAT Tregs. Second, this work also demonstrates differing roles for estrogen receptor alpha (ERα) signaling in governing ST2hi VAT Treg accumulation in lean and obese females. While ERα signaling constrained the age-dependent clonal expansion of ST2hi VAT Tregs in lean females, it protected against the loss of ST2hi VAT Treg subsets in obesity. 

Overall, this thesis demonstrates the importance cholesterol metabolism and hormone signaling in controlling the accumulation, phenotype, and function of VAT Tregs at steady state and during obesity. 

Table of Contents

CHAPTER I: INTRODUCTION 3

SECTION 1: OBESITY AND METABOLIC INFLAMMATION 3

SECTION 2: THE ONTOGENY, DEVELOPMENT, AND FUNCTION OF VISCERAL ADIPOSE TISSUE REGULATORY T CELLS 8 

SECTION 3: THE REGULATION OF SYSTEMIC AND T CELL CHOLESTEROL METABOLISM 46

SECTION 4: REFERENCES 63

CHAPTER II: OBESITY RESHAPES REGULATORY T CELLS IN THE VISCERAL ADIPOSE TISSUE BY DISRUPTING CELLULAR CHOLESTEROL HOMEOSTASIS 76

SECTION 1: ABSTRACT 76

SECTION 2: INTRODUCTION 76

SECTION 3: RESULTS 78

SECTION 4: DISCUSSION 103

SECTION 5: MATERIALS AND METHODS 108

SECTION 6: SUPPLEMENTARY FIGURES 122

SECTION 7: ACKNOWLEDGEMENTS AND AUTHOR CONTRIBUTIONS 136

SECTION 8: REFERENCES 137

CHAPTER III: ESTROGEN RECEPTOR α PROTECTS AGAINST OBESITY -INDUCED METABOLIC DYSFUNCTION BY REGULATING VAT TREGS 143

SECTION 1: ABSTRACT 143

SECTION 2: INTRODUCTION 144

SECTION 3: RESULTS 146

SECTION 4: DISCUSSION 158

SECTION 5: MATERIALS AND METHODS 160

SECTION 6: SUPPLEMENTARY FIGURES 168

SECTION 7: ACKNOWLEDGEMENTS AND AUTHOR CONTRIBUTIONS 169

SECTION 8: REFERENCES 170

CHAPTER IV: CONCLUSIONS 173

SECTION 1: REMAINING QUESTIONS IN VAT TREG CHOLESTEROL METABOLISM 173

SECTION 2: REMAINING QUESTIONS IN THE REGULATION OF VAT TREGS BY ESTROGEN SIGNALING 180

SECTION 3: CONCLUDING REMARKS 183

SECTION 4: REFERENCES 184

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Immunology and Molecular Pathogenesis
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, General Biology, Cell Biology, Molecular
Stichwort	obesity estrogen metabolic disease cholesterol biology metabolism cell immunometabolism inflammation Treg immunology immune system adipose
Committee Chair / Thesis Advisor	Chaoran Li, Emory University
Committee Members	Mandy L. Ford, Emory University Rheinallt Jones, Emory University Rabindra Tirouvanziam, Emory University Christopher Scharer, Emory University

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