The Fate Choice Between Effector and Memory T Cell Lineages: Asymmetry, Signal Integration, and Feedback to Create Bistability

Abstract

CD8⁺ T cells clear primary infections with intracellular pathogens and provide long-term immunity against reinfection. Two different types of CD8⁺ T cells are responsible for these functions: short-lived effector T cells and memory T cells. The cellular relationship between these two types of CD8⁺ T cells has been subject to much investigation. Both cell types can derive from a single naïve CD8⁺ T cell precursor. Their generation requires a fate choice early during a T cell response. As a result, two populations of T cells emerge. One of these consists of terminally differentiated short-lived effector T cells. The other contains cells able to develop into long-lived memory T cells. A foundation for development of these two populations may be laid during the first division of an activated naïve T cell precursor, as a consequence of asymmetric segregation of fate-determining factors into the daughter cells. Nonetheless, the binary choice between the two lineages is strongly influenced by signals, which ensure that the differentiation process is matched with the needs posed by the infection. Here, we will discuss the genetic and metabolic programs governing differentiation of these two lineages as well as the processes leading to their induction and consolidation to create bistability. These processes involve extensive lateral inhibition between the programs as well as positive feedback between the genetic programs and the signaling pathways responsible for their induction. These features will be highlighted by discussing the role of the Notch signaling pathway in guiding the decision between the two lineages.

Keywords: Asymmetric cell division; CD8 T cell memory; Memory precursor cells; Notch; Terminal effector T cells; Transcription factors.