On the Role of Glucocorticoid Signaling in the Differentiation of Virus-Specific CD8+ T cell memory

Abstract

CD8+ T cells (cytotoxic T lymphocytes or killer T cells) are a crucial component of the vertebrate immune system, responsible for clearing intracellular infections by killing infected cells. Upon recruitment by antigen-presenting cells, virus-specific CD8+ T cells transition through three phases during the course of an infection: expansion, contraction, and memory. The expansion phase is characterized by extensive transcriptional and functional changes within T cells, enabling them to acquire effector functions and migrate to the site of infection. After the infection is cleared, changes in the microenvironment initiate the contraction phase, during which approximately 90–95% of effector cells die via apoptosis. The remaining 5-10% of initial responders survive as long-lived memory cells, providing long-term protection from reinfection. These dynamic changes throughout a CD8+ T cell response suggest the existence of decision-making mechanisms within the cells that allow them to transition from the effector to the memory state. Since this transition involves moving from a highly active effector state to a quiescent memory state, inhibitory receptors play a significant role in the process. This thesis investigates the role of inhibitory signaling via the glucocorticoid receptor (NR3C1) in the differentiation of virus-specific CD8+ T cell memory. We demonstrate that signaling through NR3C1 is essential for facilitating the transition of responding CD8+ T cells from effector to memory states. Inhibition of this signaling, either using the competitive inhibitor mifepristone or shRNA-mediated knockdown of the glucocorticoid receptor, attenuated memory transition and the homeostatic turnover capability of virus-specific CD8+ T cells, indicating the essential role of glucocorticoid signaling in memory transition. Conversely, exposure to dexamethasone during resolving infections with influenza A virus or γ-herpesvirus promoted the conversion of effector cells into memory cells. This effect was achieved by modulating cellular metabolism, reducing the accumulation of reactive oxygen species (ROS), and improving cellular health. Reduced ROS levels coincided with increased expression of Bcl2, enhancing cell survival. The generated virus-specific memory CD8+ T cells were efficiently recalled upon secondary infection, leading to improved control of the challenge. Interestingly, the memory enhancing effect was most evident at low doses of dexamethasone, suggesting that tightly regulated glucocorticoid signaling within effector CD8+ T cells is critical for optimal memory differentiation. This thesis thus highlights glucocorticoid signaling as a key switch that suppresses effector programming and initiates memory differentiation, thereby supporting the effector-to-memory transition of virus specific CD8+ T cells.