Fig. 1. Pharmacologic targets for the enhancement of CD8⁺ T cell memory formation.

The activity of AMPK can be modulated by the AMP:ATP ratio or triggered by the biguanide metformin, resulting in inhibition of mTORC1 as well as augmentation of fatty acid oxidation and increased transcriptional activity of FOXO protein. FOXO protein acts in tandem with intranuclear binding partners to regulate gene transcription, but its binding partners involved in the modulation of pro-memory genes are incompletely elucidated. The PI3K-AKT pathway is activated by cytokine receptor engagement as well as T cell receptor and co-stimulatory receptor signaling (not shown) resulting in the downstream activation of mTORC1. PI3K-AKT activity can phosphorylate FOXO protein, promoting its cytosolic sequestration (not shown). PI3K can be inhibited by LY294002 or a number of small molecules which have recently entered clinical trials. In addition to indirect inhibition through modulation of upstream targets, mTORC1 may also be directly inhibited by rapamycin and its analogs. The activity of GSK-3β inhibits mTORC1 through activation of TSC2 as well as targets β-catenin for proteasomal degradation. Inhibition of GSK-3β using TWS119 mimics Wnt signaling by promoting β-catenin accumulation and translocation into the nucleus, where it binds to partners including LEF and TCF to promote gene transcription. PTEN, phosphatase and tensin homolog; PDK1, pyruvate dehydrogenase kinase 1; Rheb, Ras homolog enriched in brain; GβL, G protein beta subunit–like; 4E-BP1, phosphorylated heat- and acid-stable protein regulated by insulin 1; p70S6K, p70 ribosomal protein S6 kinase 1; APC, adenomatous polyposis coli; CK1α, casein kinase 1, alpha 1; Dvl, disheveled; LRP5/6, low-density lipoprotein receptor–related protein 5/6.