Molecular regulation of CD8+ T cell stemness and function

Thesis (Ph.D.)--University of Washington, 2024 ; To robustly defend the body against disease, the immune system needs to rapidly generate large, heterogeneous populations of specialized cells in response to stimuli. In this dissertation, I will focus on a subtype of adaptive immune cells, cytotoxic CD8+ T cells. Upon recognition of foreign proteins from infected and malignant cells, these cells migrate to the required tissue location to perform their effector functions, and importantly, the majority of these cells need to terminally differentiate and die after the threat is cleared to prevent immunopathology. However, a remarkable ability of the adaptive immune system is the memory recall response to past threats, whereby a small population of the responding cells with pathogen specificity are set aside and remain quiescent and stem-like so that they can be long-lived. These memory cells can then mount faster and stronger responses if the same threat reemerges. In this dissertation, I will focus on how CD8+ T cells exert this population level control. In Chapter 1, I will briefly review the literature on CD8+ T cell differentiation and introduce the scope of this work. In Chapter 2 and Chapter 3, I will focus on cell-intrinsic regulation of a key gene necessary for T cell stemness, Tcf7. In Chapter 4, I will focus on the extrinsic signals that control CD8+ T cell differentiation: antigen stimulation, co-stimulation, and cytokine signaling, and building tools to probe these stimuli in multiplexed experiments. And finally, in Chapter 5, I will briefly discuss how these insights and tools can be used to develop improved immunotherapies.