Role of PI3K/Akt signaling in memory CD8 T cell differentiation

The clonal expansion, differentiation into effectors and establishing an immunological memory are crucial components of the adaptive immune response. Following the initial encounter with a pathogen, clonal CD8 T cell expansion yields at least two distinct populations of effector cells, short-lived effector cells (SLECs) and memory precursor effector cells (MPECs). SLECs are the terminally differentiated cells, which play an active role in pathogen clearance and undergo apoptosis once the pathogen is eliminated. In contrast, MPECs persist and give rise to self-renewing memory cells. These memory CD8 T cells maintain a state of heightened alertness and are poised to rapidly respond and swiftly clear the pathogen upon antigen re-encounter. As one of the goals of vaccination is to induce the development of these memory CD8 T cells, understanding the cellular and molecular basis of memory cell differentiation is critical to rational vaccine design. It is clear that memory differentiation is complex and involves multiple interrelated signaling pathways. It is influenced by factors such as the strength and duration of antigen receptor signaling and concurrent exposure to cytokines. Several signaling pathways that influence T cell fate have been recently described, and many culminate in the differential expression of specific transcription factors. Unfortunately, the mechanisms underlying the coordination and confluence of these signaling pathways remain largely unknown. In this review, we will discuss the role of the phosphatidylinositol 3-kinase signaling pathway as a central signaling node, and the function of Akt as a rheostat in orchestrating the differentiation of memory CD8 T cells.