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

Abstract

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.

Keywords: FOXO; PI3K/Akt; differentiation; mTOR; memory T cell; metabolism.

FIGURE 1

Activation and function of PI3K/Akt signaling in CD8 T cell. Upon engagement of the TCR by peptide/MHC I complex, PI3 kinase (PI3K) is activated in CD8 T cells. Signals from costimulation, cytokines, and chemokines can also activate the PI3K. At the plasma membrane, activated PI3K phosphorylates PIP2 to generate PIP3, which recruit PH domain-containing proteins such as Akt and PDK1. Full activation of the Ser/Thr kinase Akt requires phosphorylations by PDK1 and mTORC2. In the cytosol, Akt phosphorylates and inhibits TSC1/2, a negative regulatory complex of mTORC1, which in turn promotes mTORC1-mediated protein synthesis and cell growth through modulating S6K and 4E-BP. Cytosolic Akt also inhibits GSK3, and regulates glucose metabolism and the canonical Wnt/β-catenin pathway. In addition, Akt translocates to the nucleus, and triggers the nuclear exclusion of FOXO transcription factors that are important for cell quiescence and apoptosis. AMPK senses cellular energy status by interacting with ADP/AMP and LKB1 and regulates cellular metabolism by antagonizing mTORC1-mediated glycolysis.

FIGURE 2

A model for orchestration of CD8 T cell differentiation by the PI3K/Akt pathway. Signals resulting from engagement of cell surface receptors including TCR, co-stimulatory molecules, and cytokine receptors converge to activate Akt, and the magnitude of Akt activation is a function of the cumulative signal strength from these receptors. Increase in the magnitude of Akt activation progressively drives cytotoxic T lymphocytes (CTLs) toward terminal differentiation. We propose a model where balanced Akt activation fosters development of effector functions without impeding the differentiation of MPECs and their descendent memory CD8 T cells. However, activation of Akt above a certain threshold drives differentiation of CD8 T cells into terminal effectors at the expense of MPECs by paralyzing a multitude of cell survival mechanisms including incapacitation of FOXO and the Wnt/β-catenin pathways, and stimulation of the mTOR pathway. Thus, Akt functions as a cellular fulcrum controlling distinct facets of the program that governs differentiation of antigen-activated CD8 T cells into terminal effector cells or memory CD8 T cells.