TUMOR NECROSIS FACTOR FAMILY-ASSOCIATED DYSREGULATION OF NAÏVE AND EFFECTOR CD4+ T CELL CHROMATIN ACCESSIBILITY IN SYSTEMIC LUPUS ERYTHEMATOSUS

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Degree type
Doctor of Philosophy (PhD)
Graduate group
Immunology
Discipline
Immunology and Infectious Disease
Genetics and Genomics
Subject
Autoimmunity
CD4 T cell
Epigenetics
Lupus
SLE
TNFa
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2023
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Hart, Andrew
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Abstract

Systemic lupus erythematosus is a prototypic autoimmune disease that results from theinappropriate targeting of immune cells to self-antigens, namely nuclear components. The integrated dysfunction of multiple immune cells contributes to the onset, progression, and pathology of SLE. CD4+ T cells have been implicated in the etiology and pathogenesis of lupus because of the strong association of class II HLA gene haplotypes with disease. Additionally, several murine lupus models require CD4+ T cells for the disease to manifest and SLE autoantibodies exhibit features associated with CD4+ T cell help. Although a genetic component contributes to SLE etiology, genetics alone cannot explain the heterogeneous penetrance of different susceptibility alleles and the epidemiological features of disease. Therefore, environmental effects and epigenetic regulation have been proposed as an intermediary which cooperate with appropriate susceptibility alleles in different immune cells to result in broken tolerance and autoimmunity. The status of epigenetic regulation in CD4+ T cells in lupus is incomplete and several gaps in our understanding persist. To fill these gaps in knowledge, I performed analyses to measure chromatin accessibility in discrete lupus CD4+ T cell subsets, including naïve CD4+ T cells and previously unstudied circulating Tfh populations. The findings of this work reveal that naïve and circulating Tfh lineage CD4+ T cells in lupus patients have a distinct chromatin accessibility profile relative to healthy individuals. Cytokine signals, specifically those of the TNF family, correlate with changes to chromatin accessibility and transcription in lupus CD4+ T cell populations. Finally, single-cell chromatin profiling of the naïve CD4+ T cell compartment revealed a ubiquitous chromatin dysregulation across naïve subpopulations and implicated altered chromatin in the dysfunctional activation and differentiation of CD4+ T cells. Collectively this work expands upon previous knowledge of how lupus CD4+ T cells are epigenetically regulated to include new cell subsets and demonstrates an association between TNF signaling and lupus chromatin architecture that may provide novel insights into disease mechanisms.

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Laufer, Terri, M
Date of degree
2023
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