The Regulation of CD8+ T Cell Fate by Transcription Factor Binding and Chromatin Accessibility
CD8+ T cells fight viral infections and other intracellular pathogens by identifying and destroying infected cells. CD8+ T cells, like all cells, take on different cell states which determine their behavior. This dissertation examines how epigenetic mechanisms such as chromatin accessibility and transcription factor binding regulate transcription, and consequently CD8+ T cell state. The particular CD8+ T cell states that I examine in this dissertation are: Naive (quiescent cells), Effector (cells actively fighting infection), Memory (cells that remain after infection is cleared, ready to fight recurrence of same infection), and Exhausted (cells with weakened cytotoxic function due to prolonged encounter with a particular antigen).
Chapter One introduces CD8+ T cells, regulation of transcription, and some of the high-throughput sequencing assays used later in the text to study CD8+ T cells. Chapter Two describes some of the computational tools I developed to process and infer useful information from high-throughput sequencing data. Chapter Three presents evidence that the chromatin of Exhausted CD8+ T cells differs from that of normal T cells, and demonstrates that these differences have functional consequences by validating an exhaustion-specific enhancer for PD-1, an important immunotherapy target. Chapter Four presents evidence that Batf and Irf4 work together to remodel chromatin and affect the binding of key CD8+ T cell transcription factors during the transition from naive to effector cell state.