Epigenetic gene regulation in B and T lymphocytes and its role in cellular activation, differentiation, and autoimmune disease Restricted; Files Only

Rose, James (Summer 2024)

Permanent URL: https://etd.library.emory.edu/concern/etds/n583xw628?locale=en
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Abstract

Nearly all eukaryotic cells, including lymphocytes of the adaptive immune system, regulate gene expression in part through epigenetic mechanisms. Complex networks of genes, transcription factor proteins, and epigenetic modulators work together to control how a cell reacts to its environment, undergoes prescribed cellular development, and ultimately perform functions necessary to sustain multicellular life. Here we apply a genome-wide analysis of transcript expression as well as the epigenetic landscapes of B and T cells in two different contexts. First, this work delves into the distinct transcriptomic and epigenomic profiles of human memory T cell subsets (TCM, TEM, and TEMRA). Through RNA sequencing and chromatin accessibility assays, this work reveals a progressive gradient of gene expression and chromatin changes from naïve to memory subsets. Key findings include the identification of metabolic adaptations and the role of transcription factors in mediating specific epigenetic changes—termed patterned accessibility regions—which enhance memory T cells' responsiveness to antigen re-encounters. These results highlight how epigenetic remodeling supports the specialized functions of memory T cell subsets, offering potential targets for enhancing vaccine efficacy and developing immunotherapies that leverage these epigenetic modifications. Next, we focus on B cells involved in systemic lupus erythematosus (SLE), a chronic autoimmune disease characterized by inflammation and autoantibody production. This chapter examines the epigenetic landscape of resting naïve (rN) B cells in SLE patients, comparing active and inactive disease. We identify persistent epigenetic alterations in IFN response genes and transcriptional differences in activation and cytokine signaling pathways, even during disease remission. These findings suggest that lasting epigenetic reprogramming in B cells occurs during the progression of SLE and suggests disease activity as one factor capable of modulating the previously described molecular signatures of this autoimmune disease. Finally, we expand this work by looking for such signatures in other autoimmune diseases. Much of the SLE signature in rN B cells appears to be unique to this disease, with some modest shared aspects detected in this cell type isolated from diseases such as ANCA Associated Vasculitis (AAV) and Dermatomyositis. Ultimately this work reveals aspects of the system-wide epigenetic regulation involved in lymphocyte function and its impact on normal immune responses as well as their dysregulation during autoimmune diseases.

Table of Contents

Chapter 1: Introduction   9

The discovery of lymphocytes & their role in adaptive immunity   10

The activation of lymphocytes   11

The adaptive lymphocyte receptors   11

B cell activation   12

T cell activation   14

Lymphocyte differentiation & memory   15

Effector cells   16

Memory cells   17

Epigenetic control of lymphocyte gene expression   19

Epigenetics at the molecular and system scale   19

Epigenetics in lymphocyte differentiation   21

Epigenetics in immune memory   24

Autoimmune disease & lymphocyte tolerance   26

Autoimmunity   26

B cell tolerance and autoreactivity   27

Epigenetics in autoimmune disease   29

Dissertation overview   31

Chapter 2: Distinct transcriptomic and epigenomic modalities underpin human memory T cell subsets and their activation potential   33

Abstract   34

Introduction   34

Results   36

The shared transcriptional programs of human CD4+and CD8+ MTC   36

Resting TEM/TEMRA cells exhibit progressively greater transcriptional differentiation from naïve progenitors than TCM   39

MTC subsets exhibit distinct migration and metabolism characteristics   42

The chromatin landscape of memory subsets correlates with transcriptional differentiation   46

Differentiated chromatin between MTC subsets is enriched for bZIP, HMG, T-box, and bHLH transcription factor motifs   49

bHLH Family Factors AHR and HIF1A potentially regulate different environmental responses in CD8+ TCM and TEM MTC subsets   52

Genes that are uniquely upregulated in stimulated memory subset cells include Induced and Augmented transcripts   55

Augmented gene expression is correlated with epigenetic changes introduced by earlier activation of naïve cells   58

PAR contain distinct sets of transcription factor motifs that segregate T cells by lineage and memory subtype   61

Discussion   64

Methods   70

Supporting Data   78

Chapter 3: Clinically inactive SLE resting naïve B cells retain distinct transcriptomes and alterations to the epigenome   94

Abstract   95

Introduction   96

Results   98

Resting and activated B cell subtypes are altered by SLE disease and disease activity   98

SLE rN B cells express an abnormal transcriptome in patients with low disease activity   102

Type I IFN response genes, TLR, and BCR signaling genes differentiate rN B cells in active SLE   103

Alternative cytokine signaling gene expression distinguishes inactive SLE   106

Epigenetic alterations to IFN response and TLR regulation loci remain accessible during disease remission   110

Unique and shared transcription factor motifs in inactive and active SLE epigenomes   113

MEF2C and E2A/E2-2 factors likely regulate inactive SLE specific gene sets   115

Discussion   117

Methods   123

Supporting Data   128

Chapter 4: Work in progress   142

Introduction   143

Results & Discussion   144

Supporting Data   150

Chapter 5: Discussion   153

References   161

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