Regulation of Effector and Exhausted CD8⁺ T Cell Fates

Abstract

The adaptive immune system protects the body against a wide range of threats by mountingspecific immune responses tailored towards pathogens. Cytotoxic CD8⁺ T cells, a population within the adaptive immune system, play a crucial role in clearing infections by eliminating infected or malignant cells. Depending on the infectious contexts and external stimuli, CD8⁺ T cells differentiate into different functional states. Upon antigen encounter, during an acute infection, CD8⁺ T cells differentiate into short-lived effector states with cytolytic activity as well as long-lasting memory cells that persist after infection clearance and can mount rapid and strong responses upon re-challenge. In a chronic context, persistent antigen stimulation drives CD8⁺ T cells into an exhausted state, characterized by reduced effector function, loss of self-renewal and dysfunctional properties. T cell exhaustions are often linked with poor clinical prognosis and impaired pathogen clearance. In this thesis, I will focus on understanding how differences in antigen affinity and dosage affect CD8⁺ T cell effector differentiation decisions and understand the epigenetic mechanisms underlying their terminal differentiation and exhaustion fate commitment. In Chapter 1, I will briefly introduce the immune system and CD8⁺ T cells. In Chapter 2, I will focus on how CD8⁺ T cells perceive the affinity of pMHC to regulate their effector gene expression. And finally, in Chapter 3, I will discuss the epigenetic molecular mechanisms involved in fate commitment.