Targeting memory T cell metabolism to improve immunity

Abstract

Vaccination affords protection from disease by activating pathogen-specific immune cells and facilitating the development of persistent immunologic memory toward the vaccine-specific pathogen. Current vaccine regimens are often based on the efficiency of the acute immune response, and not necessarily on the generation of memory cells, in part because the mechanisms underlying the development of efficient immune memory remain incompletely understood. This Review describes recent advances in defining memory T cell metabolism and how metabolism of these cells might be altered in patients affected by mitochondrial diseases or metabolic syndrome, who show higher susceptibility to recurrent infections and higher rates of vaccine failure. It discusses how this new understanding could add to the way we think about immunologic memory, vaccine development, and cancer immunotherapy.

Figure 1. Metabolic pathways in naive, effector, and memory T cells.

(A) Schematic of the dynamic of T cell immune response upon primary and secondary infection, depicting T cell differentiation from Tn, to Teff, and Tm cells. (B) Metabolic features of naive, effector, and memory T cells. Briefly, naive T cells are metabolically quiescent, relying on basal levels of OXPHOS for their energetic needs. Upon activation, effector T cells become highly metabolically active, increasing their substrate uptake together with glycolysis and OXPHOS. During memory T cell differentiation, metabolism rewires to a more quiescent state in which FAO and OXPHOS sustain T cell survival and energetic requirements. (C) Illustrations of the different mitochondrial morphology and ultrastructure observed in T cell subtypes. Mouse Tn cells and in vitro–differentiated IL-15 Tm cells show elongated mitochondria, while in vitro–differentiated IL-2 Teff cells display fragmented mitochondria. IL-2 Teff cells show wider cristae structure compared with the tight and elongated structure observed in IL-15 Tm cells. FAS, fatty acid synthesis.

Figure 2. Metabolic features of different memory T cell subsets.

Different Tm cell subsets preferentially use different substrates. Although they mainly rely on FAO for their energy demands, Tcm and Trm cells differ in the substrate of choice. Ex vivo Tcm cells and in vitro–generated IL-15–cultured Tcm cells engage an apparently futile cycle with the uptake of glucose used to generate fatty acids that are subsequently burned by FAO. These Tcm cells take up a lower amount of fatty acid compared with Teff or Trm cells and can even survive in a lipid-depleted medium (75). Conversely, Trm cells are able to acquire a greater amount of fatty acids directly from the microenvironment. Tem cells are relatively more metabolically active, as they are able to use multiple substrates to fuel glycolysis and OXPHOS.

Figure 3. Metabolic interventions in cancer immunotherapy.

Three main scenarios for metabolic interventions in the context of cancer immunotherapy can be imagined: (A) In vitro preconditioning to prime T cell metabolism before autologous in vivo transfer. One caveat to consider in this approach is the loss of the induced preconditioning upon T cell transfer in vivo. (B) Systemic administration of drugs that alter tumor and T cell metabolism. A limitation of this strategy is the potential for the development of systemic side effects. (C) Targeted delivery of metabolic modulators directly in the TME or administration of precursor drugs selectively activated in the TME could potentially overcome the issues described for the first two approaches.