Control of stemness in CD8 T cell differentiation

Abstract

T cell stemness enables continual generation of cytotoxic effector cells from a self-renewing pool of multipotent progenitors. After an acute infection, memory T cells persist for years in a quiescent state and upon rechallenge, rapidly reconstitute an entire expanded T cell response. In chronic infection and cancer, characterized by progression of functional cytotoxic T cells to dysfunctional exhausted cells, stem-like progenitors provide a continual source of cytotoxic cells to fuel a persistent response. In both cases, the system must balance the need for differentiation to generate effector cells and for protection of the stem cell population. Different immune challenges manifest over different time scales and with variable pathogenicity, and as such, the size and characteristics of the stem cell pool that forms vary across these different challenges with distinct signaling environments. While the molecular components that control these outcomes have been exhaustively characterized, the regulatory principles by which they act remain unclear. Thus, the goal of my thesis work has been to reveal these regulatory principles using reductionist approaches that measure T cell differentiation at the clonal level, over time, and with isolation and perturbation of distinct differentiating populations under defined signaling conditions. I first provide evidence for a stochastic epigenetic gene silencing mechanism that enables robust memory formation in acute infection. I then identify cell-state and signaling context-dependent regulators of T cell stemness using a targeted screening approach across multiple phases of T cell differentiation under chronic stimulation.