Pharmacologic induction of CD8+ T cell memory: better living through chemistry

Abstract

The generation of a robust population of memory T cells is critical for effective vaccine and cell-based therapies to prevent and treat infectious diseases and cancer. A series of recent papers have established a new, cell-intrinsic approach in which small molecules target key metabolic and developmental pathways to enhance the formation and maintenance of highly functional CD8(+) memory T cells. These findings raise the exciting new possibility of using small molecules, many of which are already approved for human use, for the pharmacologic induction of immunologic memory.

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.

Fig. 2. The timing of CIMM administration affects both the phenotype and numbers of CD8⁺ memory T cells

(A) Kinetics of a prototypical primary T cell immune response. After antigenic stimulation, naïve CD8⁺ T cells undergo a multi-log clonal expansion, peaking during the first week. The majority of CD8⁺ T cells become terminally differentiated effector cells that rapidly undergo apoptosis. A minority of responding T cells (T_CM and T_EM precursors) will persist as long-lived memory T cells. (B) Eff ect of CIMM administration during the priming and expansion phase of an immune response. Provision of CIMM during the first week of a primary immune response minimally affects the total number of responding T cells at the peak of the response but yields greater numbers of memory T cell precursors, leading to increased numbers of memory T cells without altering the relative distribution of T_CMs and T_EMs. To date, the effect of metformin has yet to be directly tested during this phase. (C) Effect of CIMM administration during the contraction phase of an immune response. The provision of CIMMs after the peak of an immune response results in a more rapid acquisition of the phenotypic and functional attributes associated with central memory T cells, without changing the absolute number of persisting memory T cells. To date, the GSK-3β inhibitor TWS119 has not been tested during this phase. Curves are extrapolated from Araki et al. (4).